Substituted 1,3-thiazole compounds, their production and use

ABSTRACT

(1) A 1,3-thiazole compound of which the 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group or (2) a 1,3-thiazole compound of which the 5-position is substituted with a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group has an excellent p38 MAP kinase inhibitory activity.

This application is a U.S. national stage of PCT/JP01/02629 filed Mar.29, 2001.

TECHNICAL FIELD

The present invention relates to an excellent p38 MAP kinase inhibitor,a TNF-α production inhibitor, an adenosine receptor antagonist, and aselective phosphodiesterase IV (PDE IV) inhibitor and the like. Morespecifically, the present invention relates to a pharmaceuticalcomposition comprising a 1,3-thiazole-based compound having an activityto prevent and/or treat cytokine-mediated diseases based on a p38 MAPkinase inhibiting activity, a TNF-α production inhibiting activity, aphosphodiesterase (PDE) inhibiting activity and the like, and to preventand/or treat adenosine receptor mediated diseases based on an adenosinereceptor antagonising activity.

BACKGROUND

Cytokines such as TNF-α (tumor necrosis factor-α), IL-1 (interleukin-1)and the like are biological substances produced by various cells such asmonocytes, macrophages and the like in response to cellular stress suchas infection and the like (Koj, A., Biochim. Biophys. Acta, 1317, 84-94(1996)). These cytokines play an important role in immune reactions whenthey are present in an appropriate amount, while it is believed thatexcess. production thereof is related to a lot of inflammatory diseases(Dinarello, C. A., Curr. Opin. Immunol., 3, 941-948 (1991)). A p38 MAPkinase cloned as a homologue of a MAP kinase is concerned with controlof the production of these cytokines, and with a signal transfer systemcoupled with a receptor, so inhibition of a p38 MAP kinase provides apossibility of a remedy for inflammatory diseases (Stein, B., Anderson,D., Annual Report in Medicinal Chemistry, Bristol, J. A. (ed.), AcademicPress, 31, pp. 289 to 298, (1996)).

As examples having such a p38 MAP kinase inhibiting activity, imidazolederivatives are described in JP-A 7-50317 (WO 93/14081) and oxazolederivatives are described in JP-A 9-505055 (WO 95/13067), respectively.

On the other hand, as a thiazole-based compound, the followingcompounds, etc. are known.

1) 1,3-thiazole derivatives of the formula:

wherein R¹ represents a cycloalkyl group, a cyclic amino group, an aminogroup optionally having one or two lower alkyls, phenyls, acetyls orlower alkoxycarbonylacetyls as a substituent, an alkyl group optionallyhaving hydroxyl, carboxyl or lower alkoxycarbonyl as a substituent, or aphenyl group optionally having carboxyl, 2-carboxyethenyl or2-carboxy-1-propenyl as a substituent, R² represents a pyridyl groupoptionally having a lower alkyl as a substituent, and R³ represents aphenyl group optionally having a lower alkoxy, lower alkyl, hydroxyl,halogen or methylenedioxy as a substituent, or a salt thereof, havinganalgesic, antipyretic, anti-inflammatory, antiulcer, thromboxane A₂(TXA₂) synthase inhibitory, and antithrombotic activities (JP-A No.60-58981).

2) 1,3-thiazole derivatives of the formula:

wherein R¹ represents an alkyl group, alkenyl group, aryl group, aralkylgroup, cycloalkyl group, heterocyclic group having carbon as aconnecting moiety, or amino group, R² represents a pyridyl groupoptionally substituted with an alkyl group, and R³ represents a phenylgroup optionally having a substituent, or a salt thereof, havinganalgesic, antipyretic, anti-inflammatory, antiulcer, TXA₂ synthaseinhibitory, and antithrombotic activities (JP-A No. 61-10580).

3) 1,3-thiazole derivatives of the formula:

wherein R¹ represents an alkyl group, alkenyl group, aryl group, aralkylgroup, cycloalkyl group, heterocyclic group having carbon as aconnecting moiety, or amino group, R² represents a pyridyl groupoptionally substituted with an alkyl group, and R³ represents an arylgroup optionally having a substituent, or a salt thereof, havinganalgesic, antipyretic, anti-inflammatory, antiulcer, TXA₂ synthaseinhibitory, and antithrombotic activities (U.S. Pat. No. 4,612,321).

4) Compounds of the formula:

wherein R¹ represents phenyl optionally having a substituent, R²represents a C₁₋₆ alkyl or (CH₂)_(n)Ar (n is 0 to 2, and Ar is phenyloptionally having a substituent), R³ represents hydrogen or C₁₋₄ alkyl,R⁴ represents hydrogen, C₁₋₄ alkyl or the like, R⁵ represents hydrogenor C₁₋₄ alkyl, and R⁶ represents hydrogen, C₁₋₄ alkyl or the like, or asalt thereof, having a gastric acid secretion inhibitory activity (JP-ANo. 7-503023, WO 93/15071).

5) Compounds of the formula:

wherein R¹ represents pyridyl or the like, R² represents phenyl or thelike, R³ and R⁴ represent hydrogen or methyl, R⁵ represents methyl orthe like, and R⁶ represents hydrogen, methyl or the like, or a saltthereof, which are an anti-inflammatory agent and antiallergic agent(DE-A-3601411).

6) Compounds of the formula:

wherein R¹ represents a lower alkyl substituted with a halogen, R²represents pyridyl or the like, and R³ represents phenyl or the like, ora salt thereof, having anti-inflammatory, antipyretic, analgesic andantiallergic activities (JP-A No. 5-70446).

7) Thiazole compounds of the formula:

wherein R represents a lower alkyl group; lower haloalkyl group; lowerhydroxyalkyl group; lower alkoxy lower alkyl group; aralkyloxy loweralkyl group or the like, R¹ represents a cycloalkyl group optionallysubstituted with a lower alkyl group and the like, and R² represents anaryl group optionally having a substituent, or the like, or apharmaceutically acceptable salt thereof, having a TNF-α selectiveproduction inhibitory activity and/or IFN-γ production inhibitoryactivity (JP-A No. 11-49762).

There is a strong need to develop compounds having an excellent p38 MAPkinase inhibitory activity, TNF-α production inhibitory activity,adenosine receptor antagonizing activity and PDE IV inhibitory activity.

DISCLOSURE OF INVENTION

The present inventors have studied various compounds, and have found forthe first time that 1,3-thiazole compounds having such specificity inchemical structure that the 5-position of a 1,3-thiazole skeleton issubstituted with a 4-pyridyl group having a substituent including noaromatic group (hereinafter, sometimes abbreviated as compound (Ia)),1,3-thiazole compounds having such specificity in chemical structurethat the 5-position of a 1,3-thiazole skeleton is substituted with apyridyl group having at the position adjacent to a nitrogen atom of thepyridyl group a substituent including no aromatic group (hereinafter,sometimes abbreviated as compound (Ib)) or 1,3-thiazole compounds havingsuch specificity in chemical structure that the 5-position of a1,3-thiazole skeleton is substituted with a 4-pyridyl group having atthe position adjacent to a nitrogen atom of the 4-pyridyl group asubstituent including no aromatic group (hereinafter, sometimesabbreviated as compound (Ic)) has an unexpectedly excellent p38 MAPkinase inhibitory activity, TNF-α production inhibitory activity,adenosine receptor antagonizing activity and PDE IV inhibitory activitybased on their specific chemical structure, and is excellent also inpharmaceutical properties such as stability, leading to completion ofthe present invention based on this knowledges.

Namely, the present invention provides:

[1] A 1,3-thiazole compound of which 5-position is substituted with a4-pyridyl group having a substituent including no aromatic group,provided that the 1,3-thiazole compound is notN-[4-(3,5-dimethylphenyl)-5-(2-hydroxy-4-pyridyl)-1,3-thiazol-2-yl]acetamideor 4-[2-(acetylamino)-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridylacetate, or a salt thereof;

[2] A compound as defined in [1] which is a compound represented by theformula:

wherein R¹ represents a hydrogen atom, a hydrocarbon group optionallyhaving a substituent, a heterocyclic group optionally having asubstituent, an amino group optionally having a substituent or an acylgroup, R² represents a 4-pyridyl group having a substituent including noaromatic group, and R³ represents an aromatic group optionally having asubstituent, or a salt thereof;

[3] A 1,3-thiazole compound of which 5-position is substituted with apyridyl group having a substituent including no aromatic group, at aposition adjacent to a nitrogen atom of the pyridyl group, provided thatthe 1,3-thiazole compound is notN-[4-(3,5-dimethylphenyl)-5-(2-hydroxy-4-pyridyl)-1,3-thiazol-2-yl]acetamideor4-[2-(acetylamino)-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl-]-2-pyridylacetate, or a salt thereof;

[4] A compound as defined in [3] which is a compound represented by theformula:

wherein R^(1a) represents a hydrogen atom, a hydrocarbon groupoptionally having a substituent, a heterocyclic group optionally havinga substituent, an amino group optionally having a substituent or an acylgroup, R^(2a) represents a pyridyl group having a substituent includingno aromatic group, at a position adjacent to a nitrogen atom of thepyridyl group, and R^(3a) represents an aromatic group optionally havinga substituent, or a salt thereof;

[5] A 1,3-thiazole compound of which 5-position is substituted with a4-pyridyl group having a substituent including no aromatic group, at aposition adjacent to a nitrogen atom of the 4-pyridyl group, providedthat the 1,3-thiazole compound is notN-[4-(3,5-dimethylphenyl)-5-(2-hydroxy-4-pyridyl)-1,3-thiazol-2-yl]acetamideor 4-[2-(acetylamino)-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridylacetate, or a salt thereof;

[6] A compound as defined in any one of [1] to [5] wherein thesubstituent including no aromatic group is a halogen atom, C₁₋₃alkylenedioxy, nitro, cyano, C₁₋₆ alkyl which may be halogenated, C₂₋₆alkenyl which may be halogenated, carboxy C₂₋₆ alkenyl, C₂₋₆ alkynylwhich may be halogenated, C₃₋₈ cycloalkyl which may be halogenated, C₃₋₈cycloalkyl-C₁₋₆ alkyl, C₁₋₈ alkoxy which may be halogenated, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkoxy, hydroxy, mercapto, C₁₋₆ alkylthio which maybe halogenated, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₃₋₈cycloalkylamino, C₃₋₈ cycloalkyl-C₁₋₆ alkylamino, N—C₃₋₈cycloalkyl-N—C₁₋₆ alkylamino, formyl, carboxy, carboxy-C₂₋₆ alkenyl,carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl which may be halogenated, C₃₋₈cycloalkyl-carbonyl optionally substituted by C₁₋₆ alkyl, C₁₋₆alkoxy-carbonyl, carbamoyl, thiocarbamoyl, mono-C₁₋₆ alkyl-carbamoyl,di-C₁₋₆ alkyl-carbamoyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl,formylamino, C₁₋₆ alkyl-carbonylamino, C₃₋₈ cycloalkyl-carbonylaminowhich may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonylamino, C₁₋₆alkylsulfonylamino, C₁₋₆ alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyloxy,mono-C₁₋₆ alkyl-carbamoyloxy, di-C₁₋₆ alkyl-carbamoyloxy, 5- to7-membered aliphatic heterocyclic group containing 1 to 4 of 1 or 2kinds of hetero atoms selected from a nitrogen atom, a sulfur atom andan oxygen atom in addition to carbon atoms (this aliphatic heterocyclicgroup optionally has a substituent selected from C₁₋₆ alkyl, C₁₋₆alkyl-carbonyl and oxo), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl or agroup obtained by connecting 2 to 3 of these substituents (e.g., (i)C₁₋₆ alkyl, (ii) amino, (iii) C₁₋₆ alkylamino, (iv) C₃₋₈cycloalkylamino, (v) 5- to 7-membered aliphatic heterocyclic aminocontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, (vi) C₁₋₆alkyl-carbonyl amino, (vii) C₃₋₈ cycloalkyl-carbonylamino or (viii) 5-to 7-membered aliphatic heterocyclic-carbonyl amino containing 1 to 4hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, which is substituted, respectively, bya substituent selected from the group consisting of a halogen atom,cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₃₋₈ cycloalkyl, 5- to 7-membered aliphatic heterocyclicgroup containing 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, C₁₋₆alkyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, 5- to 7-membered aliphaticheterocyclic-carbonyl containing 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, C₃₋₈ cycloalkoxy, 5- to 7-membered aliphatic heterocyclic-oxycontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, C₁₋₆ alkylamino,C₁₋₆ alkoxy-carbonyl, C₃₋₈ cycloalkoxy-carbonyl, 5- to 7-memberedaliphatic heterocyclic-oxycarbonyl containing 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, etc.);

[7] A compound as defined in [2] or [4] wherein

(1) the hydrocarbon group optionally having a substituent is a C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₈cycloalkyl group, a C₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl group,optionally having a substituent selected from Group A of substituentsconsisting of oxo, a halogen atom, C₁₋₃ alkylenedioxy, nitro, cyano,C₁₋₆ alkyl which may be halogenated, C₂₋₆ alkenyl which may behalogenated, carboxy C₂₋₆ alkenyl, C₂₋₆ alkynyl which may behalogenated, C₃₋₈ cycloalkyl which may be halogenated, C₃₋₈cycloalkyl-C₁₋₆ alkyl, C₆₋₁₄ aryl, C₁₋₈ alkoxy which may be halogenated,C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy, hydroxy, C₆₋₁₄ aryloxy, C₇₋₁₆aralkyloxy, mercapto, C₁₋₆ alkylthio which may be halogenated, C₆₋₁₄arylthio, C₇₋₁₆ aralkylthio, amino, mono-C₁₋₆ alkylamino, mono-C₆₋₁₄arylamino, di-C₁₋₆ alkylamino, C₃₋₈ cycloalkylamino, di-C₆₋₁₄ arylamino,C₃₋₈ cycloalkyl-C₁₋₆ alkylamino, N—C₃₋₈ cycloalkyl-N—C₁₋₆ alkylamino,formyl, carboxy, C₁₋₆ alkyl -carbonyl which may be halogenated, C₃₋₈cycloalkyl-carbonyl optionally substituted by C₁₋₆ alkyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, 5- to 7-memberedheterocyclic carbonyl containing 1 to 4 of 1 or 2 kinds of hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, carbamoyl, thiocarbamoyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, mono-C₆₋₁₄ aryl-carbamoyl,di-C₆₋₁₄ aryl-carbamoyl, 5- to 7-membered heterocyclic carbamoylcontaining 1 to 4 of 1 or 2 kinds of hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, formylamino, C₁₋₆ alkyl-carbonylamino, C₃₋₈cycloalkyl-carbonylamino optionally substituted by C₁₋₆ alkyl, C₆₋₁₄aryl-carbonylamino, C₁₋₆ alkoxy-carbonylamino, C₁₋₆ alkylsulfonylamino,C₆₋₁₄ arylsulfonylamino, C₁₋₆ alkyl-carbonyloxy, C₆₋₁₄ aryl-carbonyloxy,C₁₋₆ alkoxy-carbonyloxy, mono-C₁₋₆ alkyl-carbamoyloxy, di-C₁₋₆alkyl-carbamoyloxy, mono-C₆₋₁₄ aryl-carbamoyloxy, di-C₆₋₁₄aryl-carbamoyloxy, nicotinoyloxy, isonicotinoyloxy, 5- to 10-memberedheterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms (this heterocyclic group optionally has asubstituent selected from C₁₋₆ alkyl, C₆₋₁₄ aryl, C₁₋₆ alkyl-carbonylwhich may be halogenated, 5- to 10-membered aromatic heterocyclic groupcontaining 1 to 4 of 1 or 2 kinds of hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms and oxo), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl and a groupformed by connecting 2 to 3 of these substituents (e.g., (i) C₁₋₆ alkyl,(ii) C₆₋₁₄ aryl, (iii) amino, (iv) C₁₋₆ alkyl amino, (v) C₃₋₈cycloalkylamino, (vi) C₆₋₁₄ arylamino, (vii) 5- to 7-memberedheterocyclic amino containing 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, (viii) C₁₋₆ alkyl-carbonyl amino, (ix) C₃₋₈cycloalkyl-carbonylamino, (x) C₆₋₁₄ aryl-carbonylamino or (xi) 5- to7-membered heterocyclic-carbonyl amino containing 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, which is substituted, respectively, by asubstituent selected from the group consisting of a halogen atom, cyano,hydroxy, C₁₋₆ alkoxy, C₆₋₁₄ aryloxy, C₁₋₆ alkylthio, C₆₋₁₄ arylthio,C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₃₋₈ cycloalkyl, 5- to 7-membered heterocyclic groupcontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, C₆₋₁₄ aryl, C₁₋₆alkyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, 5- to 7-memberedheterocyclic-carbonyl containing 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, C₆₋₁₄ aryl-carbonyl, C₃₋₈ cycloalkoxy, 5- to 7-memberedheterocyclic-oxy containing 1 to 4 hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms, C₁₋₆alkylamino, C₆₋₁₄ arylamino, C₁₋₆ alkoxy-carbonyl, C₃₋₈cycloalkoxy-carbonyl, 5- to 7-membered heterocyclic-oxycarbonylcontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, C₆₋₁₄aryloxycarbonyl, etc.)

(2) the heterocyclic group optionally having a substituent is a 5- to14-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds ofhetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, which optionally has a substituentselected from Group A of substituents,

(3) the acyl group is an acyl group of the formula: —(C═O)—R^(5a),—(C═O)—OR^(5a), —(C═O)—NR^(5a)R^(6a), —(C═S)-NHR^(5a),—(C═O)—N(OR^(5a))R^(6a), —(C═S)—NHOR^(5a) or —SO₂—R^(7a) (wherein R^(5a)represents {circle around (1)} a hydrogen atom, {circle around (2)} aC₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₈cycloalkyl group, a C₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl group,optionally having a substituent selected from Group A of substituents,or {circle around (3)} a 5- to 14-membered heterocyclic group containing1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, whichoptionally has a substituent selected from Group A of substituents,R^(6a) represents a hydrogen atom or a C₁₋₆ alkyl group, and R^(7a)represents {circle around (1)} a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₄ aryl group or aC₇₋₁₆ aralkyl group, optionally having a substituent selected from GroupA of substituents, or {circle around (2)} a 5- to 14-memberedheterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, which optionally has a substituent selectedfrom Group A of substituents.),

(4) the amino group optionally having a substituent is

(i) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of {circle around (1)} a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group, optionally having a substituentselected from Group A of substituents, {circle around (2)} a 5- to14-membered heterocyclic group containing 1 to 4 of 1 or 2 kinds ofhetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, which optionally have a substituentselected from Group A of substituents, {circle around (1)} an acyl groupof the formula: —(C═O)—R^(5a), —(C═O)—OR^(5a), —(C═O)—NR^(5a)R^(6a),—(C═S)—NHR^(5a), —(C═O)—N(OR^(5a))R^(6a), —(C═S)—NHOR^(5a) or—SO₂—R^(7a) (wherein each symbol is as defined above), and {circlearound (4)} a C₁₋₆ alkylidene group optionally having a substituentselected from Group A of substituents, or

(ii) a 5- to 7-membered aliphatic cyclic amino group optionallycontaining 1 to 4 of 1 or 2 kinds of hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to onenitrogen atom and carbon atoms, which optionally has a substituentselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₄ aryl, C₁₋₆alkyl-carbonyl which may be halogenated, C₁₋₆ alkoxy-carbonyl, 5- to10-membered aromatic heterocyclic group containing 1 to 4 of 1 or 2kinds of hetero atoms selected from a nitrogen atom, a sulfur atom andan oxygen atom in addition to carbon atoms, and oxo,

(5) the substituent containing no aromatic group is a halogen atom, C₁₋₃alkylenedioxy, nitro, cyano, C₁₋₆ alkyl which may be halogenated, C₂₋₆alkenyl which may be halogenated, carboxy C₂₋₆ alkenyl, C₂₋₆ alkynylwhich may be halogenated, C₃₋₈ cycloalkyl which may be halogenated, C₃₋₈cycloalkyl-C₁₋₆ alkyl, C₁₋₈ alkoxy which may be halogenated, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkoxy, hydroxy, mercapto, C₁₋₆ alkylthio which maybe halogenated, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₃₋₈cycloalkylamino, C₃₋₈ cycloalkyl-C₁₋₆ alkylamino, N—C₃₋₈cycloalkyl-N—C₁₋₆ alkylamino, formyl, carboxy, carboxy-C₂₋₆ alkenyl,carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl which may be halogenated, C₃₋₈cycloalkyl-carbonyl optionally substituted by C₁₋₆ alkyl, C₁₋₆alkoxy-carbonyl, carbamoyl, thiocarbamoyl, mono-C₁₋₆ alkyl-carbamoyl,di-C₁₋₆ alkyl-carbamoyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl,formylamino, C₁₋₆ alkyl-carbonylamino, C₃₋₈ cycloalkyl-carbonylaminowhich may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonylamino, C₁₋₆alkylsulfonylamino, C₁₋₆ alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyloxy,mono-C₁₋₆ alkylcarbamoyloxy, di-C₁₋₆ alkyl-carbamoyloxy, 5- to7-membered aliphatic heterocyclic group containing 1 to 4 of 1 or 2kinds of hetero atoms selected from a nitrogen atom, a sulfur atom andan oxygen atom in addition to carbon atoms (this aliphatic heterocyclicgroup optionally has a substituent selected from C₁₋₆ alkyl, C₁₋₆alkyl-carbonyl and oxo), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl or agroup obtained by connecting 2 to 3 of these substituents (e.g., (i)C₁₋₆ alkyl, (ii) amino, (iii) C₁₋₆ alkylamino, (iv) C₃₋₈cycloalkylamino, (v) 5- to 7-membered aliphatic heterocyclic aminocontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, (vi) C₁₋₆alkyl-carbonyl amino, (vii) C₃₋₈ cycloalkyl-carbonylamino or (viii) 5-to 7-membered aliphatic heterocyclic-carbonyl amino containing 1 to 4hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, which is substituted, respectively, bya substituent selected from the group consisting of a halogen atom,cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₃₋₈ cycloalkyl, 5- to 7-membered aliphatic heterocyclicgroup containing 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, C₁₋₆alkyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, 5- to 7-membered aliphaticheterocyclic-carbonyl containing 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, C₃₋₈ cycloalkoxy, 5- to 7-membered aliphatic heterocyclicoxycontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, C₁₋₆ alkylamino,C₁₋₆ alkoxy-carbonyl, C₃₋₈ cycloalkoxy-carbonyl, 5- to 7-memberedaliphatic heterocyclic-oxycarbonyl containing 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, etc.),

(6) the aromatic group optionally having a substituent is {circle around(1)} a C₆₋₁₄ mono-cyclic or fused poly-cyclic aromatic hydrocarbon groupoptionally having a substituent selected from Group A of substituents,or {circle around (2)} a 5- to 14-membered aromatic heterocyclic groupcontaining 1 to 4 of 1 or 2 kinds of hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms;

[8] A compound as defined in [2] or [4] wherein R¹ represents (i) ahydrogen atom, (ii) a C₁₋₆ alkyl group optionally substituted by asubstituent selected from the group consisting of a halogen atom, C₁₋₆alkoxy-carbonyl, carboxy, cyano, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl ,C₁₋₆ alkylsulfonyl, hydroxy, C₁₋₆ alkoxy and C₁₋₆ alkyl-carbonyl, (iii)a C₆₋₁₄ aryl group optionally having a substituent selected from thegroup consisting of a halogen atom and a group of the formula:—S(O)_(n)—-R^(1bb) (wherein R^(1bb) represents a C₁₋₆ alkyl group, and nrepresents an integer of 0 to 2), (iv) a C₇₋₁₅ aralkyl group, (v) anamino group optionally having one or two substituents selected from{circle around (1)} C₁₋₆ alkyl, {circle around (2)} C₁₋₆ alkyl-carbonyl,{circle around (3)} 5- to 7-membered heterocyclic-carbonyl containing 1to 4 hetero atoms selected from the group consisting of a nitrogen atom,an oxygen atom and a sulfur atom, in addition to carbon atoms,optionally substituted with a halogen atom, C₁₋₆ alkyl or C₁₋₆ alkoxy,{circle around (4)} C₆₋₁₄ aryl-carbamoyl, {circle around (5)} C₁₋₆alkyl-carbamoyl which may be halogenated, {circle around (6)} C₁₋₆alkoxy-carbonyl which may be halogenated, {circle around (7)} C₁₋₆alkoxy-carbamoyl and {circle around (8)} C₆₋₁₄ aryloxy-carbamoyl, (vi) a5- to 10-membered heterocyclic group containing 1 to 4 of 1 or 2 kindsof hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms, optionally substituted by oxo,C₁₋₆ alkyl, C₆₋₁₄ aryl or C₁₋₆ alkoxy-carbonyl, (vii) an acyl grouprepresented by the formula: —(C═O)—R^(5b) (wherein R^(5b) represents ahydrogen atom, a C₁₋₆ alkyl group which may be halogenated or a C₆₋₁₄aryl group which may be halogenated), or (viii) an acyl group represenedby the formula: —(C═O)—OR^(5c) (wherein R^(5c) represents a hydrogenatom or a C₁₋₆ alkyl group);

[9] A compound as defined in [2] or [4] wherein the substituent havingno aromatic group is

(1) a C₁₋₆ alkyl group (this C₁₋₆ alkyl may be substituted by a halogenatom, cyano, hydroxy, C₃₋₈ cycloalkyl or 5- to 7-membered aliphaticheterocyclic group containing hetero atoms selected from a nitrogenatom, an oxygen atom and a sulfur atom in addition to carbon atoms),

(2) a halogen atom,

(3) an amino group optionally having a substituent selected from thegroup consisting of the following {circle around (1)} to {circle around(7)};

{circle around (1)} a C₁₋₆ alkyl group (this C₁₋₆ alkyl group may besubstituted by a halogen atom, cyano, hydroxy, C₃₋₈ cycloalkyl or 5- to7-membered aliphatic heterocyclic group having 1 to 4 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon atoms),

{circle around (2)} a C₃₋₈ cycloalkyl group,

{circle around (3)} a C₁₋₆ alkyl-carbonyl group (this C₁₋₆alkyl-carbonyl group may be substituted by a halogen atom, cyano,hydroxy, C₃₋₈ cycloalkyl or 5- to 7-membered aliphatic heterocyclicgroup having 1 to 4 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom in addition to carbon atoms),

{circle around (4)} a C₁₋₆ alkoxy-carbonyl group,

{circle around (5)} a C₃₋₈ cycloalkyl-carbonyl group optionallysubstituted by C₁₋₆ alkyl,

{circle around (6)} a 5- to 7-membered aliphatic heterocyclic grouphaving 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atomand a sulfur atom in addition to carbon atoms (this aliphaticheterocyclic group may be substituted by C₁₋₆ alkyl or C₁₋₆alkyl-carbonyl),

{circle around (7)} a 5- to 7-membered aliphatic heterocyclic-carbonylgroup having 1 to 4 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom in addition to carbon atoms (thisaliphatic heterocyclic-carbonyl group may be substituted by C₁₋₆ alkylor C₁₋₆ alkyl-carbonyl)

(4) a 5- to 7-membered aliphatic cyclic amino group optionally furthercontaining hetero atoms selected from a nitrogen atom, an oxygen atomand a sulfur atom in addition to carbon atoms and one nitrogen atom(this aliphatic cyclic amino group may be substituted by C₁₋₆ alkyl orC₁₋₆ alkyl-carbonyl),

(5) a hydroxy group, or

(6) a C₁₋₆ alkyl-carbonyloxy group.

[10] A compound as defined in [2] or [4] wherein R³ is {circle around(1)} a C₆₋₁₄ aryl group or {circle around (2)} a 5- to 14-memberedaromatic heterocyclic group preferably containing 1 to 4 of 1 or 2 kindsof hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms, which optionally hassubstituents selected from the group consisting of C₁₋₆ alkyl which maybe halogenated, C₁₋₆ alkoxy, a halogen atom, carboxyl, C₁₋₆alkoxy-carbonyl, cyano, C₁₋₆ alkylthio and C₁₋₆ alkylsulfonyl;

[11] A compound as defined in [3] which is a compound of the formula:

wherein R^(1b) represents (i) a hydrogen atom, (ii) a C₁₋₆ alkyl groupoptionally substituted by a substituent selected from the groupconsisting of a halogen atom, C₁₋₁₆ alkoxy-carbonyl, carboxy, cyano,C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, hydroxy, C₁₋₆alkoxy and C₁₋₆ alkyl-carbonyl, (iii) a C₆₋₁₄ aryl group optionallyhaving a substituent selected from the group consisting of a halogenatom and a group of the formula: —S(O)_(n)—R^(1bb) (R^(1bb) represents aC₁₋₆ alkyl group, and n represents an integer of 0 to 2), (iv) a C₇₋₁₅aralkyl group, (v) an amino group optionally having one or twosubstituents selected from {circle around (1)} C₁₋₆ alkyl, {circlearound (2)} C₁₋₆ alkyl-carbonyl, {circle around (3)} C₁₋₆alkoxy-carbonyl, {circle around (4)} 5- to 7-memberedheterocyclic-carbonyl containing 1 to 4 hetero atoms selected from thegroup consisting of a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon atoms, optionally substituted with a halogen atom,C₁₋₆ alkyl or C₁₋₆ alkoxy, {circle around (5)} C₆₋₁₄ aryl-carbamoyl,{circle around (6)} C₁₋₆ alkyl-carbamoyl which may be halogenated,{circle around (7)} C₁₋₆ alkoxy-carbonyl which may be halogenated,{circle around (8)} C₁₋₆ alkoxy-carbamoyl and {circle around (9)} C₆₋₁₄aryloxy-carbamoyl, (vi) a 5- to 10-membered heterocyclic groupcontaining 1 to 4 of 1 or 2 kinds of hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, optionally substituted by oxo, C₁₋₆ alkyl, C₆₋₁₄ aryl, C₁₋₆alkyl-carbonyl or C₁₋₆ alkoxy-carbonyl, (vii) an acyl group representedby the formula: —(C═O)—R^(5b) (wherein R^(5b) represents a hydrogenatom, a C₁₋₆ alkyl group which may be halogenated or a C₆₋₁₄ aryl groupwhich may be halogenated), or (viii) an acyl group represented by theformula: —(C═O)—OR^(5c) (wherein R^(5c) represents a hydrogen atom orC₁₋₆ alkyl group),

R^(2b) represents a pyridyl group having at the position adjacent to anitrogen atom of the pyridyl group a substituent selected from the groupconsisting of

(1) a C₁₋₆ alkyl group (this C₁₋₆ alkyl group may be substituted by ahalogen atom, cyano, hydroxy, C₃₋₈ cycloalkyl or a 5- to 7-memberedaliphatic heterocyclic group containing hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom in addition to carbonatoms),

(2) a halogen atom,

(3) an amino group optionally having a substituent selected from thegroup consisting of the following {circle around (1)} to {circle around(7)};

{circle around (1)} a C₁₋₆ alkyl group (this C₁₋₆ alkyl group may besubstituted by a halogen atom, cyano, hydroxy, C₃₋₈ cycloalkyl or a 5-to 7-membered aliphatic heterocyclic group having 1 to 4 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon atoms)

{circle around (2)} a C₃₋₈ cycloalkyl group,

{circle around (3)} a C₁₋₆ alkyl-carbonyl group (this C₁₋₆alkyl-carbonyl group may be substituted by a halogen atom, cyano,hydroxy, C₃₋₈ cycloalkyl or a 5- to 7-membered aliphatic heterocyclicgroup having 1 to 4 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom in addition to carbon atoms),

{circle around (4)} a C₁₋₆ alkoxy-carbonyl group,

{circle around (5)} a C₃₋₈ cycloalkyl-carbonyl group optionallysubstituted by C₁₋₆ alkyl,

{circle around (6)} a 5- to 7-membered aliphatic heterocyclic grouphaving 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atomand a sulfur atom in addition to carbon atoms (this aliphaticheterocyclic group may be substituted by C₁₋₆ alkyl or C₁₋₆alkyl-carbonyl),

{circle around (7)} a 5- to 7-membered aliphatic heterocyclic-carbonylgroup having 1 to 4 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom in addition to carbon atoms (thisaliphatic heterocyclic-carbonyl group may be substituted by C₁₋₆ alkylor C₁₋₆ alkyl-carbonyl),

(4) a 5- to 7-membered aliphatic cyclic amino group optionally furthercontaining 1 to 4 hetero atoms selected from a nitrogen atom, an oxygenatom and a sulfur atom in addition to carbon atoms and one nitrogen atom(this saturated cyclic amino group may be substituted by C₁₋₆ alkyl orC₁₋₆ alkyl-carbonyl),

(5) a hydroxy group, and

(6) a C₁₋₆ alkyl-carbonyloxy group, and

R^(3b) represents {circle around (1)} a C₆₋₁₄ aryl group or {circlearound (2)} a 5- to 14-membered aromatic heterocyclic group containing 1to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, whichoptionally has a substituent selected from the group consisting of C₁₋₆alkyl which may be halogenated, C₁₋₆ alkoxy, a halogen atom, carboxyl,C₁₋₆ alkoxy-carbonyl, cyano, C₁₋₆ alkylthio and C₁₋₆ alkylsulfonyl, or asalt thereof;

[12] A compound as defined in [11] wherein the pyridyl group is a4-pyridyl group;

[13] A compound as defined in [11] wherein R^(1b) is a C₁₋₆ alkyl groupoptionally having a substituent selected from the group consisting of ahalogen atom, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyland C₁₋₆ alkylsulfonyl, R^(2b) is a 4-pyridyl group having a C₁₋₆alkyl-carbonyl-amino group or a C₃₋₈ cycloalkylamino group at theposition adjacent to a nitrogen atom of the 4-pyridyl group, R^(3b) is aC₆₋₁₄ aryl group which optionally has a substituent selected from thegroup consisting of C₁₋₆ alkyl and a halogen atom;

[14] A compound as defined in [11] wherein R^(1b) is a C₁₋₃ alkyl groupoptionally having a substituent selected from the group consisting of ahalogen atom, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyland C₁₋₆ alkylsulfonyl, R^(2b) is a 4-pyridyl group having a C₁₋₃alkyl-carbonyl-amino group or a C₃₋₈ cycloalkylamino group at theposition adjacent to a nitrogen atom of the 4-pyridyl group, R^(3b) is aphenyl group which optionally has a substituent selected from the groupconsisting of methyl and a chlorine atom;

[15] A compound as defined in [5] which is5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-4-(3-methylphenyl)-1,3-thiazole(Example 3),

[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine(Example 7-4),

2-ethyl-5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole (Example11),

5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole(Example 15),

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4(methylthio)phenyl]-1,3-thiazole(Example 16-1),

4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (Example22),

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide(Example 29-2),

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide(Example 29-4),

N-[4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide(Example 30-1),

N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide(Example 30-2),

N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide(Example 30-3),

N-[4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide(Example 30-7),

N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide(Example 30-8),

N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide(Example 30-9),

N-cyclohexyl-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine(Example 36-4),

N-cyclohexyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine(Example 36-5),

N-cyclopentyl-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine(Example 36-6),

N-cyclopentyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine(Example 36-7),

4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclohexyl-2-pyridylamine(Example 36-10),

4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclopentyl-2-pyridylamine(Example 36-11),

N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]acetamide(Example 39),

N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide(Example 42-1),

6-chloro-N-[4-(3,5-dimethylphenyl)-5-(2-methyl4-pyridyl)-1,3-thiazol-2-yl]nicotinamide(Example 44-3),

N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-6-methylnicotinamide(Example 46-3),

N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-6-methoxynicotinamide(Example 48-3),

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-(4-methylsulfinylphenyl)-1,3-thiazole(Example 54),

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole(Example 57),

5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole(Example 58-4),

N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide(Example 58-6),

N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide(Example 58-7),

N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]pivalamide(Example 58-8),

or a salt thereof;

[16] A pro-drug of a compound as claimed in any one as defined in [1] to[5];

[17] A method for producing a compound as defined in [1] or [3]comprising

(1) reacting a compound represented by the formula:

wherein Hal represents a halogen atom, R² and R³ are as defined in Claim2, or a salt thereof with a compound of the formula:

wherein R¹ is as defined in Claim 2, or a salt thereof, or

(2) reacting a compound represented by the formula:

wherein Hal represents a halogen atom, R^(2a) and R^(3a) are as definedin Claim 4, or a salt thereof with a compound represented by theformula:

wherein R^(1a) is as defined in Claim 4, or a salt thereof;

[18] A pharmaceutical composition containing the compound as claimed inany one of [1] to [5] or a prodrug thereof;

[19] The composition as defined in [18] which is a p38 MAP kinaseinhibitor;

[20] The composition as defined in [18] which is a TNF-α productioninhibitor;

[21] The composition as defined in [18] which is a composition forpreventing or treating a cytokine-madiated disease;

[22] The composition as defined in [18] which is an adenosine receptorantagonist;

[23] The composition as defined in [18] which is a composition forpreventing or treating adenosine receptor-mediated diseases;

[24] The composition as defined in [18] which is a composition forpreventing or treating asthma or allergic diseases;

[25] The composition as defined in [18] which is a composition forpreventing or treating inflammation, Addison's disease, autoimmunehemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal cordinjury, multiple sclerosis, Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis, diabetes, arthritis, toxaemias,ulcerative colitis, chronic pneumonia, pulmonary silicosis, pulmonarysarcoidosis, lung tuberculosis, cachexia, arterial sclerosis,Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemiclupus erythematosus, AIDS encephalopathy, meningitis, angina pectoris,myocardial infarction, congestive heart failure, hepatitis, transplant,dialysis hypotension or diffuse intravascular coagulation symdrome;

[26] The composition as defined in [18] which is a composition forpreventing or treating chronic rheumatoid arthritis or osteoarthritis;

[27] The composition as defined in [18] which is a composition forpreventing or treating cerebral edema, cerebrovascular disorder, headtrauma, cerebral infarction or apoplectic stroke;

[28] A method for inhibiting p38 MAP kinase which comprisesadministering an effective amount of the compound as defined in any oneof [1] to [5] or a pro-drug. thereof to mammals;

[29] A method for inhibiting TNF-α production which comprisesadministering an effective amount of the compound as defined in any oneof [1] to [5] or a pro-drug thereof to mammals;

[30] A method for antagonizing an adenosine receptor which comprisesadministering an effective amount of the compound as defined in any oneof [1] to [5] or a pro-drug thereof to mammals;

[31] A method for preventing or treating asthma or allergic diseaseswhich comprises administering an effective amount of the compound asdefined in any one of [1] to [5] or a pro-drug thereof to mammals;

[32] A method for preventing or treating inflammation, Addison'sdisease, autoimmune hemolytic anemia, Crohn's disease, psoriasis,rheumatism, spinal cord injury, multiple sclerosis, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis,toxaemias, ulcerative colitis, chronic pneumonia, pulmonary silicosis,pulmonary sarcoidosis, lung tuberculosis, cachexia, arterial sclerosis,Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemiclupus erythematosus, AIDS encephalopathy, meningitis, angina pectoris,myocardial infarction, congestive heart failure, hepatitis, transplant,dialysis hypotension or diffuse intravascular coagulation symdrome whichcomprises administering an effective amount of the compound as definedin [1] to [5] or a pro-drug thereof to mammals;

[33] A method for preventing or treating chronic rheumatoid arthritis orosteoarthritis which comprises administering an effective amount of thecompound as defined in [1] to [5] or a pro-drug thereof to mammals;

[34] A method for preventing or treating cerebral edema, cerebrovasculardisorder, head trauma, cerebral infarction or apoplectic stroke whichcomprises administering an effective amount of the compound as definedin any one of [1] to [5] or a pro-drug thereof to mammals;

[35] Use of the compound as defined in any one of [1] to [5] or apro-drug thereof for producing a p38 MAP kinase inhibitor:

[36] Use of the compound as defined in any one of [1] to [5] or pro-drugthereof for producing a TNF-α production inhibitor;

[37] Use of the compound as defined in any one of [1] to [5] or apro-drug thereof for producing an adnosine receptor antoganist;

[38] Use of the compound as defined in any one of [1] to [5] or apro-drug thereof for producing a composition for preventing or treatingasthma and allergic diseases;

[39] Use of the compound as defined in any one of [1] to [5] or apro-drug thereof for producing a composition for preventing or treatinginflammation, Addison's disease, autoimmune hemolytic anemia, Crohn'sdisease, psoriasis, rheumatism, spinal cord injury, multiple sclerosis,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,diabetes, arthritis, toxaemias, ulcerative colitis, chronic pneumonia,pulmonary silicosis, pulmonary sarcoidosis, lung tuberculosis, cachexia,arterial sclerosis, Creutzfeldt-Jakob disease, virus infection, atopicdermatitis, systemic lupus erythematosus, AIDS encephalopathy,meningitis, angina pectoris, myocardial infarction, congestive heartfailure, hepatitis, transplant, dialysis hypotension or diffuseintravascular coagulation symdrome;

[40] Use of the compound as defined in any one of [1] to [5] or apro-drug thereof for producing a composition for preventing or treatingchronic rheumatoid arthritis or osteoarthritis; and

[41] Use of the compound as defined in any one of [1] to [5] or apro-drug thereof for producing a composition for preventing or treatingcerebral edema, cerebrovascular disorder, head trauma, cerebralinfarction or apoplectic stroke.

In this specification, as the “acyl group”, for example, a acyl grouprepresented by the formula: —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶,—(C═S)—NHR⁵, —(C═O)—N(OR⁵)R⁶, —(C═S)—NHOR⁵ or —SO₂—R⁷ wherein R⁵represents a hydrogen atom, a hydrocarbon group optionally having asubstituent or a heterocyclic group optionally having a substituent, R⁶represents a hydrogen atom or a C₁₋₆ alkyl group, and R⁷ represents ahydrocarbon group optionally having a substituent or a heterocyclicgroup optionally having a substituent, etc. are exemplified.

In the above-described formulae, as the “hydrocarbon group” of the“hydrocarbon group optionally having a substituent” represented by R⁵,for example, an acyclic or cyclic hydrocarbon group (e.g., alkyl,alkenyl, alkynyl, cycloalkyl, aryl, aralkyl and the like), etc. areexemplified. Of them, an acyclic or cyclic hydrocarbon group having 1 to16 carbon atoms, etc. are preferable.

As the “alkyl”,for example, a C₁₋₆ alkyl group (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyland the like), etc. are preferable.

As the “alkenyl”, for example, a C₂₋₆ alkenyl group (e.g., vinyl, allyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl,1-methyl-2-propenyl, 2-methyl-1-propenyl and the like), etc. arepreferable.

As the “alkynyl”, for example, a C₂₋₆ alkynyl group (e.g., ethynyl,propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl and the like),etc. are preferable.

As the “cycloalkyl”, for example, a C₃₋₈ cycloalkyl group (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), etc. arepreferable.

As the “aryl” , for example, a C₆₋₄ aryl group (e.g., phenyl,1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,2-anthryl and the like), etc. are preferable.

As the “aralkyl”, for example, a C₇₋₁₆ aralkyl group (e.g., benzyl,phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and thelike), etc. are preferable.

As the “substituent” of the “hydrocarbon group optionally having asubstituent” represented by R⁵, for example, oxo, a halogen atom (e.g.,fluorine, chlorine, bromine, iodine and the like), C₁₋₃ alkylenedioxy(e.g., methylenedioxy, ethylenedioxy and the like), nitro, cyano, C₁₋₆alkyl which may be halogenated, C₂₋₆ alkenyl which may be halogenated,carboxy C₂₋₆ alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyland the like), C₂₋₆ alkynyl which may be halogenated, C₃₋₈ cycloalkylwhich may be halogenated, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, C₆₋₁₄ aryl (e.g.,phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl and the like), C₁₋₈ alkoxy which may behalogenated, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy (e.g.,ethoxycarbonylmethyloxy and the like), hydroxy, C₆₋₁₄ aryloxy (e.g.,phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like), C₇₋₁₆ aralkyloxy(e.g., benzyloxy, phenethyloxy and the like), mercapto, C₁₋₆ alkylthiowhich may be halogenated, C₆₋₁₄ arylthio (e.g., phenylthio,1-naphthylthio, 2-naphthylthio and the like), C₇₋₁₆ aralkylthio (e.g.,benzylthio, phenethylthio and the like), amino, mono-C₁₋₆ alkylamino(e.g., methylamino, ethylamino and the like), mono-C₆₋₁₄ arylamino(e.g., phenylamino, 1-naphthylamino, 2-naphthylamino and the like),di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino, ethylmethylaminoand the like), C₃₋₈ cycloalkylamino (e.g., cyclopentylamino,cyclohexylamino and the like), di-C₆₋₄ arylamino (e.g., diphenylaminoand the like), C₃₋₈ cycloalkyl-C₁₋₆ alkylamino (e.g.,cyclopentylmethylamino, cyclohexylmethylamino, cyclopentylethylamino,cyclohexylethylamino and the like), N—C₃₋₈ cycloalkyl-N—C₁₋₆ alkylamino(N-cyclopentyl-N-methylamino, N-cyclohexyl-N-methylamino,N-cyclopentyl-N-ethylamino, N-cyclohexyl-N-ethylamino and the like),formyl, carboxy, carboxy-C₂₋₆ alkenyl, carboxy-C₁₋₆ alkyl, C₁₋₆alkyl-carbonyl which may be halogenated (e.g., acetyl, propionyl,pivaloyl and the like), C₃₋₈ cycloalkyl-carbonyl optionally substitutedby C₁₋₆ alkyl such as methyl, ethyl, etc. (e.g., cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl-cyclohexyl-carbonyland the like), C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like),C₆₋₁₄ aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl and thelike), C₇₋₁₆ aralkyl-carbonyl (e.g., phenylacetyl, 3-phenylpropionyl andthe like), C₆₋₁₄ aryloxy-carbonyl (e.g., phenoxycarbonyl and the like),C₇₋₁₆ aralkyloxy-carbonyl (e.g., .benzyloxycarbonyl,phenethyloxycarbonyl and the like), 5- to 7-membered heterocycliccarbonyl containing 1 to 4 of 1 or 2 kinds of hetero atoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl,morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl,pyrrolidin-1-ylcarbonyl and the like), carbamoyl, thiocarbamoyl,mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, andthe like), di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl,diethylcarbamoyl, ethylmethylcarbamoyl and the like), mono- or di-C₆₋₁₄aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl and the like), mono- or di-5- to 7-memberedheterocyclic carbamoyl containing 1 to 4 of 1 or 2 kinds of hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and thelike), C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl and thelike), C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl and thelike), C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl and the like), C₆₋₁₄ arylsulfinyl (e.g.,phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like),formylamino, C₁₋₆ alkyl-carbonylamino (e.g., acetylamino,propionylamino, pivaloylamino and the like), C₃₋₈cycloalkyl-carbonylamino optionally substituted by C₁₋₆ alkyl (e.g.,cyclopropylcarbonylamino, cyclopentylcarbonylamino,cyclohexylcarbonylamino and the like), C₆₋₁₄ aryl-carbonylamino (e.g.,benzoylamino, naphthoylamino and the like), C₁₋₆ alkoxy-carbonylamino(e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,butoxycarbonylamino and the like), C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino, ethylsulfonylamino and the like), C₆₋₁₄arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino,1-naphthylsulfonylamino and the like), C₁₋₆ alkyl-carbonyloxy (e.g.,acetoxy, propionyloxy and the like), C₆₋₁₄ aryl-carbonyloxy (e.g.,benzoyloxy, naphthylcarbonyloxy and the like), C₁₋₆ alkoxy-carbonyloxy(e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy and the like), mono-C₁₋₆ alkyl-carbamoyloxy (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-C₁₋₆alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy andthe like), mono- or di-C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy and the like), nicotinoyloxy,isonicotinoyloxy, 5- to 10-membered heterocyclic group containing 1 to 4of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms (e.g. 5- to7-membered aliphatic heterocyclic group, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl and the like) optionally having a substituent, sulfo,sulfamoyl, sulfinamoyl, sulfenamoyl, a group obtained by connecting twoor more (e.g., 2 to 3) of these substituents (e.g., (i) C₁₋₆ alkyl, (ii)C₆₋₁₄ aryl, (iii) amino, (iv) C₁₋₆ alkylamino, (v.) C₃₋₈cycloalkylamino, (vi) C₆₋₁₄ arylamino, (vii) 5- to 7-memberedheterocyclic amino containing 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, (viii) C₁₋₆ alkyl-carbonyl amino, (ix) C₃₋₈cycloalkyl-carbonylamino, (x) C₆₋₁₄ aryl-carbonylamino or (xi) 5- to7-membered heterocyclic-carbonyl amino containing 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, which is substituted, respectively, by asubstituent selected from the group consisting of a halogen atom, cyano,hydroxy, C₁₋₆ alkoxy, C₆₋₁₄ aryloxy, C₁₋₆ alkylthio, C₆₋₁₄ arylthio,C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₃₋₈ cycloalkyl, 5- to 7-membered heterocyclic groupcontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, C₆₋₁₄ aryl, C₁₋₆alkyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, 5- to 7-memberedheterocyclic-carbonyl containing 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, C₆₋₁₄ aryl-carbonyl, C₃₋₈ cycloalkoxy, 5- to 7-memberedheterocyclic-oxy containing 1 to 4 hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms, C₁₋₆alkylamino, C₆₋₁₄ arylamino, C₁₋₆ alkoxy-carbonyl, C₃₋₈cycloalkoxy-carbonyl, 5- to 7-membered heterocyclic-oxycarbonylcontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, C₆₋₁₄aryloxycarbonyl, etc.) (sometimes referred to as Group A ofsubstituents).

The above-mentioned “hydrocarbon group” may have, for example, the 1 to5, preferably 1 to 3 above-mentioned substituents at substitutablepositions, and when the number of the substituent is 2 or more, they maybe the same or different.

As the above-mentioned “C₁₋₆ alkyl which may be halogenated”, forexample, C₁₋₆ alkyl(e.g.,methyl,ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) which mayhave 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine and the like), etc. are exemplified. As specificexamples thereof, methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl, etc. are exemplified.

As the above-mentioned “C₂₋₆ alkenyl which may be halogenated”, forexample, C₂₋₆ alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-1-yl,4-penten-1-yl, 5-hexen-1-yl and the like) which may have 1 to 5,preferably 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine,iodine and the like), etc. are exemplified.

As the above-mentioned “C₂₋₆ alkynyl which may be halogenated”, forexample, C₂₋₆ alkynyl (e.g., 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yland the like) which may have 1 to 5, preferably 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like), etc. areexemplified.

As the above-mentioned “C₃₋₈ cycloalkyl which may be halogenated”, forexample, C₃₋₈ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like) which may have 1 to 5, preferably 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like),etc. are exemplified. As specific examples thereof, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl,2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc. areexemplified.

As the above-mentioned “C₁₋₈ alkoxy which may be halogenated”, forexample, C₁₋₈ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like) whichmay have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like), etc. are exemplified. Asspecific examples thereof, methoxy, difluoromethoxy, trifluoromethoxy,ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.are exemplified.

As the above-mentioned “C₁₋₆ alkylthio which may be halogenated”, forexample, C₁₋₆ alkylthio (e.g., methylthio, ethylthio, propylthio,isopropylthio, butylthio, sec-butylthio, tert-butylthio and the like)which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like), etc. are exemplified. Asspecific examples thereof, methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc. are exemplified.

As the “5- to 7-membered aliphatic heterocyclic group” of theabove-mentioned “5- to 7-membered aliphatic heterocyclic groupoptionally having a substituent”, for example, 5- to 7-memberedaliphatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms are exemplified, and as specific examplesthereof, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl,3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl,thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl,hexahydroazepin-1-yl, etc. are exemplified.

As the “substituent” of the above-mentioned “5- to 7-membered aliphaticheterocyclic group optionally having a substituent”, for example, 1 to 3of C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like), C₆₋₁₄ aryl (e.g.,phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl and the like), C₁₋₆ alkyl-carbonyl (e.g.,acetyl, propionyl and the like) which may be halogenated, C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl), 5- to 10-membered aromatic heterocyclic group (e.g.,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl,3-indolyl, 2benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), oxo, etc. areexemplified.

As the “heterocyclic group” of the “heterocyclic group optionally havinga substituent” represented by R⁵, for example, a 5- to 14-membered(monocyclic, bicyclic or tricyclic) heterocyclic ring which may contain1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms areexemplified, preferably, mono-valent groups obtained by removing any onehydrogen atom from (i) a 5- to 14-membered (preferably, 5- to10-membered) aromatic heterocyclic ring, (ii) a 5- to 10-memberedaliphatic heterocyclic ring or (iii) a 7- to 10-membered bridgedheterocyclic ring, etc. are exemplified.

As the above-mentioned 5- to 14-membered (preferably, 5- to 10-membered)aromatic heterocyclic ring, for example, an aromatic heterocyclic ringsuch as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole,benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene,furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine,isoquinoline, quinoline, phthalazine, naphthylidine, quinoxaline,quinazoline, cinnoline, carbazole, β-carboline, phenanthridine,acridine, phenazine, thiazole, isothiazole, phenothiazine, isooxazole,furazane, phenoxazine and the like, or rings formed by fusing theserings (preferably, monocyclic ring) with 1 or plural (preferably, 1 or2) aromatic rings (for example, benzene ring and the like), etc. areexemplified.

As the above-mentioned “5- to 10-membered aliphatic heterocyclic ring”,for example, pyrrolidine, imidazoline, pyrazolidine, pyrazoline,piperidine, piperazine, morpholine, thiomorpholine, dioxazole,oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole, etc.are exemplified.

As the above-mentioned “7- to 10-membered bridged heterocyclic ring”,for example, quinuclidine, 7-azabicyclo [2.2.1] heptane, etc. areexemplified.

The above-mentioned “heterocyclic group” is preferably a 5- to14-membered (preferably, 5- to 10membered) (monocyclic or bicyclic)heterocyclic group which contains preferably 1 to 4 of 1 or 2 kinds ofhetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms. Specifically, an aromatic heterocyclicgroup such as, for example, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, pirazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl,2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo [b]furanyl, .3-benzo[b]furanyl and the like,and aliphatic heterocylic groups such as, for example, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 3-oxazolidinyl, 1-imidazolidinyl,2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl,4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl,1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholin0 and the like,etc. are exemplified.

Of them, for example, a 5- or 6-membered heterocyclic group containing 1to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms are further preferable.Specifically, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-furyl, 3-furyl, pirazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl,3-isothiazolyl, 3-isooxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 3-oxazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl,4-imidazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl,piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl,2-piperazinyl, morpholino, thiomorpholino, etc. are exemplified.

As the “substituent” of the above-mentioned “heterocyclic groupoptionally having a substituent”, for example, the same moieties as forthe “substituent” of the above-mentioned “hydrocarbon group optionallyhaving a substituent” represented by R⁵, etc. are exemplified.

The above-mentioned “heterocyclic group” may have, for example, 1 to 5,preferably 1 to 3 of the above-mentioned substituents at substitutablepositions, and when the number of the substituent is 2 or more, they maybe the same or different.

As the “C₁₋₆ alkyl group” represented by R⁶, for example, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,hexyl, etc. are exemplified.

As the “hydrocarbon group optionally having a substituent” and“heterocyclic group optionally having a substituent” represented by R⁷,for example, the above-mentioned “hydrocarbon group optionally having asubstituent” and “heterocyclic group optionally having a substituent”represented by R⁵ are exemplified, respectively.

As the “hydrocarbon group optionally having a substituent” representedby R¹ and R^(1a), for example, the “hydrocarbon group optionally havinga substituent” represented by R⁵ is exemplified.

As the “heterocyclic group optionally having a substituent” representedby R¹ and R^(1a), for example, the “heterocyclic group optionally havinga substituent” represented by R⁵ is exemplified.

As the “amino group optionally having a substituent” represented by R¹and R^(1a), for example, (1) an amino group optionally having 1 or 2substituents and (2) a cyclic amino group optionally having asubstituent are exemplified.

As the “substituent” of the above-mentioned “(1) amino group optionallyhaving 1 or 2 substituents”, for example, a hydrocarbon group optionallyhaving a substituent, a heterocyclic group optionally having asubstituent, an acyl group, an alkylidene group optionally having asubstituent, etc. are exemplified. As the “hydrocarbon group optionallyhaving a substituent” and “heterocyclic group optionally having asubstituent”, for example, the same moieties as for the above-mentioned“hydrocarbon group optionally having a substituent” and “heterocyclicgroup optionally having a substituent” represented by R⁵ areexemplified, respectively.

As the “alkylidene group” of the above-mentioned “alkylidene groupoptionally having a substituent”, for example, C₁₋₆ alkylidene (e.g.,methylidene, ethylidene, propylidene and the like), etc. areexemplified. As the “substituent” of the above-mentioned “alkylidenegroup optionally having a substituent”, for example, 1 to 5, preferably1 to 3 of the same moieties as for the “substituent” of theabove-mentioned “hydrocarbon group optionally having a substituent”represented by R⁵ are exemplified.

When the number of the “substituent” of the above-mentioned “amino groupoptionally having 1 or 2 substituents” is two, these substituents may bethe same or different.

As the “cyclic amino group” of the above-mentioned “(2) cyclic aminogroup optionally having a substituent”, for example, a 5- to 7-memberedaliphatic cyclic amino group which may contain 1 to 4 of 1 or 2 kinds ofhetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to one nitrogen atom and carbon atoms are exemplified,and as specific examples thereof, 1-pyrrolidinyl, piperidino,1-piperazinyl, morpholino, thiomorpholino, hexahydroazepin-1-yl,1-imidazolidinyl, 2,3-dihydro-(1H)-imidazolyl,tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl,3,4-dihydro-1(2H)-pyrimidinyl, etc. are exemplified. As the“substituent” of the “cyclic amino group optionally having asubstituent”, for example, 1 to 3 of the same moieties as for the“substituent” of the “5- to 7-membered aliphatic heterocyclic groupoptionally having a substituent” described in detail as the“substituent” of the “hydrocarbon group optionally having a substituent”represented by R⁵.

As specific examples of the 5- to 7-membered aliphatic cyclic aminogroup having one oxo, for example, 2-oximidazolidin-1-yl,2-oxo-2,3-dihydro-1-H-imidazol-1-yl, 2-oxoteterahydro-1(2H)-pyrimidinyl,2-oxo-3,6-dihydro-1(2H)-pyrimidinyl,2-oxo-3,4-dihydro-1(2H)-pyrimidinyl, 2-oxopyrrolidin-1-yl,2-oxopiperidino, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl,2-oxo-2,3,4,5,6,7-hexahydroazepin-1-yl, etc. are exemplified.

R¹ or R^(1a) is preferably an alkyl group optionally having asubstituent, an aryl group optionally having a substituent, an aminogroup optionally having a substituent, a heterocyclic group optionallyhaving a substituent, an acyl group represented by the formula;—(C═O)—R⁵ (wherein R⁵ is as defined above), an acyl group represented bythe formula: —(C═O)—OR⁵ (wherein R⁵ is as defined above), or the like.

As the “alkyl group optionally having a substituent”, for example, aC₁₋₆ alkyl group (preferably, methyl, ethyl, propyl, butyl and the like)optionally having 1 to 5 substituents selected from a halogen atom,carboxy, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl, C₁₋₆ alkylthio,C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, and the like, etc. arepreferably exemplified.

As the above-mentioned “aryl group optionally having a substituent”, forexample, a C₆₋₁₄ aryl group (preferably, phenyl and the like) optionallyhaving 1 to 5 substituents selected from a halogen atom, C₁₋₆ alkylthio,C₆₋₁₄ arylthio, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, C₁₋₆alkylsulfonyl, C₆₋₁₄ arylsulfonyl, carboxy and the like, etc. arepreferably exemplified.

As the above-mentioned “amino group optionally having a substituent”, anamino group optionally having 1 or 2 acyl represented by the formula:—(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵, —(C═O)—N(OR⁵)R⁶,—(C═S)—NHOR⁵ or —SO₂—R⁷ (wherein each symbol is as defined above), etc.are preferably exemplified.

Further preferably, R¹ is an amino group optionally having 1 or 2 acylsrepresented by the formula: —(C═O)—R⁵ or —(C═O)—NR⁵R⁶ (wherein eachsymbol is as defined above), etc. are exemplified.

As the “heterocyclic group” of the “heterocyclic group optionally havinga substituent”, for example, a 5- to 14-membered (monocyclic, bicyclicor tricyclic) heterocyclic group which contain 1 to 4 of 1 or 2 kinds ofhetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms are used, and of them, a 5- to10-membered aliphatic heterocyclic group, a 5- to 7-membered aromaticheterocyclic group, etc. are preferable.

As the “substituent” of the “heterocyclic group optionally having asubstituent”, for example, an oxo group, a C₁₋₆ alkyl group (e.g.,methyl, ethyl, etc.), a C₆₋₁₄ aryl group (e.g., phenyl, etc.), a C₁₋₆alkyl-carbonyl group (e.g., acetyl, etc.), a C₁₋₆ alkoxy-carbonyl group(e.g., methoxycarbonyl, ethoxycarbonyl, etc.) and the like are used, andthe number of substituents is 1 to 3.

As R⁵ of the “acyl group represented by the formula: —(C═O)—R⁵”, ahydrogen atom, a hydrocarbon group optionally having a substitutent andan aromatic heterocyclic group optionally having a substituent arepreferable, and particularly, {circle around (1)} a hydrogen atom,{circle around (2)} a C₁₋₆ alkyl group which may be halogenated (e.g.,methyl, ethyl, propyl, trifluoromethyl, etc.), {circle around (3)} aC₆₋₁₄ aryl group which may be halogenated (e.g., phenyl, naphthyl,fluorophenyl, chlorophenyl, etc.), {circle around (4)} a 5- to7-membered aromatic heterocyclic group (e.g., pyridyl, thienyl,pyrrolyl, furyl, pyridazinyl, pyrimidinyl, etc.) which may besubstituted by a halogen atom (e.g., fluorine, chlorine, bromine, etc.),optionally halogenated C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,trifluoromethyl, etc.), C₁₋₆ alkoxy group (e.g., methoxy, ethoxy,propoxy, butoxy, etc.), and the like are preferable.

As R⁵ of the “acyl group represented by the formula: —(C═O)—OR⁵”, ahydrogen atom and a hydrocarbon group optionally substituted arepreferable, and particularly, a hydrogen atom and a C₁₋₆ alkyl group(e.g., methyl, ethyl, propyl, etc.), and the like are preferable.

As R¹ or R^(1a), (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group optionallysubstituted by a substituent selected from the group consisting of ahalogen atom, C₁₋₆ alkoxy-carbonyl, carboxy, cyano, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, hydroxy, C₁₋₆ alkoxy and C₁₋₆alkyl-carbonyl, (iii) a C₆₋₁₄ aryl group optionally having a substituentselected from the group consisting of a halogen atom and a group of theformula: —S(O)_(n)—R^(1bb) (R^(1bb) represents a C₁₋₆ alkyl group, and nrepresents an integer of 0 to 2), (iv) a C₇₋₁₅ aralkyl group, (v) anamino group optionally having-one or two substituents selected from{circle around (1)} C₁₋₆ alkyl, {circle around (2)} C₁₋₆ alkyl-carbonyl,{circle around (3)} 5- to 7-membered heterocyclic-carbonyl containing 1to 4 hetero atoms selected from the group consisting of a nitrogen atom,an oxygen atom and a sulfur atom in addition to carbon atoms, optionallysubstituted with a halogen atom, C₁₋₆ alkyl or C₁₋₆ alkoxy, {circlearound (4)} C₆₋₁₄ aryl-carbamoyl, {circle around (5)} C₁₋₆alkyl-carbamoyl which may be halogenated, {circle around (6)} C₁₋₆alkoxy-carbonyl which may be halogenated, {circle around (7)} C₁₋₆alkoxy-carbamoyl and {circle around (8)} C₆₋₁₄ aryloxy-carbamoyl, (vi) a5- to 10-membered heterocyclic group containing 1 to 4 of 1 or 2 kindsof hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms, optionally substituted by oxo,C₁₋₆ alkyl , C₆₋₁₄ aryl, C₁₋₆ alkoxy-carbonyl or C₁₋₆ alkyl-carbonyl,(vii) an acyl group represented by the formula: —(C═O)—R^(5b) (whereinR^(5b) represents a hydrogen atom, a C₁₋₆ alkyl group which may behalogenated or a C₆₋₁₄ aryl group which may be halogenated), or (viii)an acyl group represented by the formula: —(C═O)—OR^(5c) (wherein R^(5c)represents a hydrogen atom or a C₁₋₆ alkyl group), and the like aresuitable.

As the C₁₋₆ alkyl group represented by R¹ or R^(1a), for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, etc. are used, and particularly, C₁₋₄ alkylgroups such as methyl, ethyl, propyl, butyl and the like are preferable.

As the halogen atom which is a substituent of the C₁₋₆ alkyl grouprepresented by R¹ or R^(1a), for example, a fluorine atom, a chlorineatom, a bromine atom and an iodine atom are preferable.

As the C₁₋₆ alkoxy-carbonyl which is a substituent of the C₁₋₆ alkylgroup represented by R¹ or R^(1a), for example, methoxycarbonyl,ethoxycarbonyl and the like are preferable.

As the C₁₋₆ alkylthio which is a substituent of the C₁₋₆ alkyl grouprepresented by R¹ or R^(1a), for example, methylthio, ethylthio and thelike are preferable.

As the C₁₋₆ alkylsulfinyl which is a substituent of the C₁₋₆ alkyl grouprepresented by R¹ or R^(1a), for example, methylsulfinyl, ethylsulfinyland the like are preferable.

As the C₁₋₆ alkylsulfonyl which is a substituent of the C₁₋₆ alkyl grouprepresented by R¹ or R^(1a), for example, methylsulfonyl, ethylsulfonyland the like are preferable.

As the C₁₋₆ alkoxy which is a substituent of the C₁₋₆ alkyl grouprepresented by R¹ or R^(1a), for example, methoxy, ethoxy, propoxy andthe like are preferable.

As the C₁₋₆ alkyl-carbonyl which is a substituent of the C₁₋₆ alkylgroup represented by R¹ or R^(1a), for example, acetyl, propionyl andthe like are preferable.

As the C₁₋₆ alkyl group represented by R^(1bb), for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl, etc. are used, and of them, C₁₋₄ alkyl groups such asmethyl, ethyl, propyl, butyl and the like are preferable, and methyl isparticularly preferable.

As the C₆₋₁₄ aryl group represented by R¹ or R^(1a), for example,phenyl, naphthyl, etc. are preferable, and of them, phenyl isparticularly preferable.

As the halogen atom which is a substituent of the C₆₋₁₄ aryl grouprepresented by R¹ or R^(1a), a fluorine atom, a chlorine atom, a bromineatom and an iodine atom are used.

As the C₇₋₁₅ aralkyl group represented by R¹ or R^(1a), for example,phenyl-C₁₋₃ alkyl groups such as benzyl, phenylethyl, phenylpropyl andthe like are preferable.

As the C₁₋₆ alkyl group which is a substituent of an amino grouprepresented by R¹ or R^(1a), for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.are used, and of them, C₁₋₃ alkyl groups such as methyl, ethyl, propyland the like are preferable, particularly, methyl is preferable.

As the C₁₋₆ alkyl-carbonyl which is a substituent of an amino grouprepresented by R¹ or R^(1a), for example, a C₁₋₃ alkyl-carbonyl groupsuch as acetyl, propionyl and the like are preferable.

As the “5- to 7-membered heterocyclic-carbonyl containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygenatom and a sulfur atom in addition to carbon atoms” which is asubstituent of an amino group represented by R¹ or R^(1a), for example,a 5- to 7-membered heterocyclic (e.g., furyl, thienyl, pyrrolyl,pyridyl, pyrimidinyl, pyridazinyl and the like)-carbonyl groupcontaining 1 or 2 hetero atoms selected from the group consisting of anitrogen atom, an oxygen atom and a sulfur atom, etc. are preferable. Asthe substituent of the heterocyclic group of this heterocyclic-carbonylgroup, a halogen atom such as a chlorine atom and the like, C₁₋₆ alkylgroup such as methyl, ethyl and the like, and C₁₋₆ alkoxy such asmethoxy, ethoxy and the like are preferable.

As the C₆₋₁₄ aryl-carbamoyl which is a substituent of an amino grouprepresented by R¹ or R^(1a), for example, phenyl-carbamoyl, etc. arepreferable.

As the C₁₋₆ alkyl-carbamoyl which may be halogenated which is asubstituent of an amino group represented by R¹ or R^(1a), for example,methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl optionally substitutedby a halogen atom (e.g., chlorine atom) and the like are preferable.

As the C₁₋₆ alkoxy-carbonyl which may be halogenated which is asubstituent of an amino group represented by R¹ or R^(1a), for example,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl optionally substitutedby halogen atoms (e.g., a chlorine atom) and the like are preferable.

As the C₁₋₆ alkoxy-carbamoyl which is a substituent of an amino grouprepresented by R¹ or R^(1a), for example, methoxycarbamoyl,ethoxycarbamoyl, propoxycarbamoyl and the like are preferable.

As the C₆₋₁₄ aryloxy-carbamoyl which is a substituent of an amino grouprepresented by R¹ or R^(1a), for example, phenyloxy-carbamoyl and thelike are preferable.

As the 5- to 10-membered aliphatic heterocyclic group represented by R¹or R^(1a), for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,3-oxazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl,morpholino, thiomorpholino and the like, are used, and of them,4-piperidyl, 1-piperazinyl, 3-oxazolidinyl, 1-imidazolidinyl and thelike are preferable.

As the 5- to 10-membered aliphatic heterocyclic group optionallysubstituted by oxo, C₁₋₆ alkyl (preferably, methyl, ethyl), C₆₋₁₄ aryl(preferably, phenyl), C₁₋₆ alkyl-carbonyl (preferably, acetyl) or C₁₋₆alkoxy-carbonyl (preferably, methoxycarbonyl, ethoxycarbonyl)represented by R¹ or R^(1a), 1-methyl-4-piperidyl,4-methyl-1-piperazinyl, 2-oxo-3-oxazolidinyl, 2-oxo-1-imidazolidinyl,2-oxo-3-phenyl-1-imidazolidinyl and the like are preferable.

As R^(5b) of the formula: —(C═O)—R^(5b) represented by R¹ or R^(1a), ahydrogen atom, a C₁₋₆ alkyl group which may be halogenated by a fluorineatom, a chlorine atom and the like (e.g., methyl, ethyl,trifluoromethyl, etc.), a C₆₋₁₄ aryl group which may be halogenated by afluorine atom, a chlorine atom and the like (e.g., phenyl, naphthyl,fluorophenyl, chlorophenyl, etc.) are preferable.

As R^(5c) of the formula: —(C═O)—OR^(5c), a hydrogen atom and a C₁₋₃alkyl group (methyl, ethyl, etc.) are preferable.

As the “substituent containing no aromatic group” carried by a4-pyridylgroup substituted at the 5-position of a compound (Ia), the “substituentcontaining no aromatic group” substituted at the position adjacent to anitrogen atom of a pyridyl group substituted at the 5-position of acompound (Ib) the “substituent containing no aromatic group” substitutedat the position adjacent to a nitrogen atom of a 4-pyridyl groupsubstituted at the 5-position of a compound (Ic), the “substituentcontaining no aromatic group” of the “4-pyridyl group having asubstituent containing no aromatic group” represented by R², and “thesubstituent containing no aromatic group” of the “pyridyl group havingat the position adjacent to a nitrogen atom of the pyridyl group asubstituent containing no aromatic group” represented by R^(2a), forexample, a halogen atom (e.g., fluorine, chlorine, bromine, iodine andthe like), C₁₋₃ alkylenedioxy (e.g., methylenedioxy, ethylenedioxy andthe like), nitro, cyano, C₁₋₆ alkyl which may be halogenated, C₂₋₆alkenyl which may be halogenated, carboxy C₂₋₆ alkenyl (e.g.,2-carboxyethenyl, 2-carboxy-2-methylethenyl and the like), C₂₋₆ alkynylwhich may be halogenated, C₃₋₈ cycloalkyl which may be halogenated, C₃₋₈cycloalkyl-C₁₋₆ alkyl, C₁₋₈ alkoxy which may be halogenated, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkoxy (e.g., ethoxycarbonylmethyloxy and thelike), hydroxy, mercapto, C₁₋₆ alkylthio which may be halogenated,amino, mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino and thelike), di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino,ethylmethylamino and the like), C₃₋₈ cycloalkylamino (e.g.,cyclopentylamino, cyclohexylamino and the like), C₃₋₈ cycloalkyl-C₁₋₆alkyl amino (e.g., cyclopentylmethylamino, cyclohexylmethylamino,cyclopentylethylamino, cyclohexylethylamino and the like), N—C₃₋₈cycloalkyl-N—C₁₋₆ alkylamino (e.g., N-cyclopentyl-N-methylamino,N-cyclohexyl-N-methylamino, N-cyclopentyl-N-ethylamino,N-cyclohexyl-N-ethylamino and the like), formyl, carboxy, carboxy-C₂₋₆alkenyl, carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl which may behalogenated (e.g., acetyl, propionyl, 2,2,2-trifluoroacetyl,3,3,3-trifluoropropionyl, 2,2-difluoropropionyl and the like), C₃₋₈cycloalkyl-carbonyl optionally substituted by C₁₋₆ alkyl (e.g.,cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,1-methyl-cyclohexyl-carbonyl and the like), C₁₋₆ alkoxy-carbonyl (e.g.,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyland the like), carbamoyl, thiocarbamoyl, mono-C₁₋₆ alkyl-carbamoyl(e.g., methylcarbamoyl, ethylcarbamoyl, and the like), di-C₁₋₆alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl and the like), C₁₋₆ alkylsulfonyl (e.g.,methylsulfonyl, ethylsulfonyl and the like), C₁₋₆ alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl and the like), formylamino, C₁₋₆alkyl-carbonylamino (e.g., acetylamino, propionylamino, pivaloylaminoand the like), C₃₋₈ cycloalkyl-carbonylamino optionally substituted byC₁₋₆ alkyl (e.g., cyclopropylcarbonylamino, cyclopentylcarbonylamino,cyclohexylcarbonylamino, 1-methyl-cyclohexylcarbonylamino and the like),C₁₋₆ alkoxy-carbonylamino (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and thelike), C₁₋₆ alkylsulfonylamino (e.g., methylsulfonylamino,ethylsulfonylamino and the like), C₁₋₆ alkyl-carbonyloxy (e.g., acetoxy,propionyloxy and the like), C₁₋₆ alkoxy-carbonyloxy (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy and the like), mono-C₁₋₆ alkylcarbamoyloxy (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy and the like),di-C₁₋₆-alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy and the like), 5- to 7-membered aliphaticheterocyclic group having a substituent, sulfo, sulfamoyl, sulfinamoyl,sulfenamoyl, a group formed by connecting 2 to 3 of these substituents(e.g., (i) C₁₋₆ alkyl, (ii) amino, (iii) C₁₋₆ alkylamino, (iv) C₃₋₈cycloalkylamino, (v) 5- to 7-membered aliphatic heterocyclic aminocontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, (vi) C₁₋₆ alkyl-carbonyl amino, (vii) C₃₋₈ cycloalkyl-carbonylamino or (viii) 5- to7-membered aliphatic heterocyclic-carbonyl amino containing 1 to 4hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, which is substituted, respectively, bya substituent selected from the group consisting of a halogen atom,cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₃₋₈ cycloalkyl, 5- to 7-membered aliphatic heterocyclicgroup containing 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, C₁₋₆alkyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, 5- to 7-membered aliphaticheterocyclic-carbonyl containing 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, C₃₋₈ cycloalkoxy, 5- to 7-membered aliphatic heterocyclic-oxycontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, C₁₋₆ alkylamino,C₁₋₆ alkoxy-carbonyl, C₃₋₈ cycloalkoxy-carbonyl, 5- to 7-memberedaliphatic heterocyclic-oxycarbonyl containing 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, etc.) and the like are exemplified.

As the above-mentioned “C₁₋₆ alkyl which may be halogenated”, forexample, C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) which mayhave 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine and the like), etc. are exemplified. As specificexamples thereof, methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl, etc. are exemplified.

As the above-mentioned “C₂₋₆ alkenyl which may be halogenated”, forexample, C₂₋₆ alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-1-yl,4-penten-1-yl, 5-hexen-1-yl and the like) which may have 1 to 5,preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine and the like), etc. are exemplified.

As the above-mentioned “C₂₋₆ alkynyl which may be halogenated”, forexample, C₂₋₆ alkynyl (e.g., 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yland the like) which may have 1 to 5, preferably 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like), etc. areexemplified.

As the above-mentioned “C₃₋₈ cycloalkyl which may be halogenated”, forexample, C₃₋₈ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like) which may have 1 to 5, preferably 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like),etc. are exemplified. As specific examples thereof, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl,2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc. areexemplified.

As the above-mentioned “C₁₋₁₈ alkoxy which may be halogenated”, forexample, C₁₋₈ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like) whichmay have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like), etc. are exemplified. Asspecific examples thereof, methoxy, difluoromethoxy, trifluoromethoxy,ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.are exemplified.

As the above-mentioned “C₁₋₆ alkylthio which may be halogenated”, forexample, C₁₋₆ alkylthio (e.g., methylthio, ethylthio, propylthio,isopropylthio, butylthio, sec-butylthio, tert-butylthio and the like)which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like), etc. are exemplified. Asspecific examples thereof, methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc. are exemplified.

As the “5- to 7-membered aliphatic heterocyclic group” of theabove-mentioned “5- to 7-membered aliphatic heterocyclic groupoptionally having a substituent”, for example, 5- to 7-memberedaliphatic heterocyclic group containing 1 to 4 of 1 or 2 kinds of heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms are exemplified, and as specific examplesthereof, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl,3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl,thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl,hexahydroazepin-1-yl, etc. are exemplified.

As the “substituent” of the above-mentioned “5- to 7-membered aliphaticheterocyclic group optionally having a substituent”, for example, 1 to 3of C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like), C₁₋₆ alkyl-carbonyl(e.g., acetyl, propionyl and the like), oxo, etc. are exemplified.

Provided that, when

(i) R¹ or R^(1a) is an acetylamino group, and R³ or R^(3a) is a3,5-dimethylphenyl group,

(ii) R¹ or R^(1a) is a C₁₋₆ alkyl-carbonylamino group, and R³ or R^(3a)is a C₆₋₁₄ aryl group substituted by a C₁₋₆ alkyl group, or

(iii) R¹ or R^(1a) is an amino group optionally having a substituent,and R3 or R^(3a) is an aromatic hydrocarbon group optionally having asubstituent,

there are exemplified, as the “substituent containing no aromaticgroup”, a halogen atom (e.g., fluorine, chlorine, bromine, iodine andthe like), C₁₋₃ alkylenedioxy (e.g., methylenedioxy, ethylenedioxy andthe like), nitro, cyano, C₁₋₆ alkyl which may be halogenated, C₂₋₆alkenyl which may be halogenated, carboxy C₂₋₆ alkenyl (e.g.,2-carboxyethenyl, 2-carboxy-2-methylethenyl and the like), C₂₋₆ alkynylwhich may be halogenated, C₃₋₈ cycloalkyl which may be halogenated, C₃₋₈cycloalkyl-C₁₋₆ alkyl, C₁₋₈ alkoxy which may be halogenated, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkoxy (e.g., ethoxycarbonylmethyloxy and thelike), mercapto, C₁₋₆ alkylthio which may be halogenated, amino,mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino and the like),di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino, ethylmethylaminoand the like), C₃₋₈ cycloalkylamino (e.g., cyclopentylamino,cyclohexylamino and the like), C₃₋₈ cycloalkyl-C₁₋₆ alkyl amino (e.g.,cyclopentylmethylamino, cyclohexylmethylamino and the like)., N—C₃₋₈cycloalkyl-N—C₁₋₆ alkylamino (e.g., N-cyclopentyl-N-methylamino,N-cyclohexyl-N-methylamino, N-cyclopentyl-N-ethylamino,N-cyclohexyl-N-ethylamino and the like), formyl, carboxy, carboxy-C₂₋₆alkenyl, carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl (e.g., acetyl,propionyl and the like), C₃₋₈ cycloalkyl-carbonyl optionally substitutedby C₁₋₆ alkyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, 1-methyl-cyclohexyl-carbonyl and the like), C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl and the like), carbamoyl, thiocarbamoyl, mono-C₁₋₆alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, and the like),di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl and the like), C₁₋₆ alkylsulfonyl (e.g.,methylsulfonyl, ethylsulfonyl and the like), C₁₋₆ alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl and the like), formylamino, C₁₋₆alkyl-carbonylamino (e.g., acetylamino, propionylamino, pivaloylaminoand the like), C₃₋₈ cycloalkyl-carbonylamino optionally substituted byC₁₋₆ alkyl (e.g., cyclopropylcarbonylamino, cyclopentylcarbonylamino,cyclohexylcarbonylamino and the like), C₁₋₆ alkoxy-carbonylamino (e.g.,methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,butoxycarbonylamino and the like), C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino, ethylsulfonylamino and the like), C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy and the like), mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy and thelike), di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy and the like), 5- to 7-membered aliphaticheterocyclic group optionally having a substituent (preferably, 5- to7-membered aliphatic heterocyclic group having 1 to 4 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon atoms), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyland the like are exemplified. Further, a group obtained by connectingtwo or more (e.g., (i) C₁₋₆ alkyl, (ii) amino, (iii) C₁₋₆ alkylamino,(iv) C₃₋₈ cycloalkylamino, (v) 5- to 7-membered aliphatic heterocyclicamino containing 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, (vi) C₁₋₆alkyl-carbonyl amino, (vii) C₃₋₈ cycloalkyl-carbonylamino or (viii) 5-to 7-membered aliphatic heterocyclic-carbonyl amino containing 1 to 4hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, which is substituted, respectively, bya substituent selected from the group consisting of a halogen atom,cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkyl sulfonyl, C₃₋₈ cycloalkyl, 5- to 7-membered aliphatic heterocyclicgroup containing 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, C₁₋₆alkyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, 5- to 7-membered aliphaticheterocyclic-carbonyl containing 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, C₃₋₈ cycloalkoxy, 5- to 7-membered aliphatic heterocyclic-oxycontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, C₁₋₆ alkylamino,C₁₋₆ alkoxy-carbonyl, C₃₋₈ cycloalkoxy-carbonyl, 5- to 7-memberedaliphatic heterocyclic-oxydarbonyl containing 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, etc.), etc. can also be used as a substituent.

Among these substituents, specifically, 1 to 3, preferably 1 or2substituents selected from the following (1) to (6), particularly (1) to(4) are preferably used.

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, preferablya C₁₋₄ alkyl group such as methyl, ethyl, propyl, butyl and the like):this C₁₋₆ alkyl group may be substituted by a halogen atom, cyano,hydroxy, C₃₋₈ cycloalkyl or a 5- to 7-membered aliphatic heterocyclicgroup containing hetero atoms selected from a nitrogen atom, an oxygenatom and a sulfur atom in addition to carbon atoms (e.g.,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl,3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl,4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino,2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and thelike),

(2) a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom,iodine atom),

(3) an amino group optionally having a substituent selected from thegroup consisting of the following {circle around (1)} to {circle around(7)}:

{circle around (1)} a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and thelike, preferably C₁₋₃ alkyl groups such as methyl, ethyl, propyl and thelike), this C₁₋₆ alkyl group may be substituted by a halogen atom,cyano, hydroxy, C₃₋₈ cycloalkyl or 5- to 7-membered aliphaticheterocyclic group containing 1 to 4 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom in addition to carbonatoms (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl,3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl,thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl,hexahydroazepin-1-yl and the like),

{circle around (2)} a C₃₋₈ cycloalkyl group (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like),

{circle around (3)} a C₁₋₆ alkyl-carbonyl group.(e.g., acetyl,propionyl, butyryl, valeryl, isovaleryl, 2-methylpropionyl, pivaloyl andthe like), this C₁₋₆ alkyl-carbonyl group may be substituted by ahalogen atom, cyano, hydroxy, C₃₋₈ cycloalkyl or 5- to 7-memberedaliphatic heterocyclic group optionally containing 1 to 4 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon atoms (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl,1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 4-piperazinyl, morpholino,2-morpholinyl, 3-morpholinyl, thiomorpholino, 2-thiomorpholinyl,3-thiomorpholinyl, hexahydroazepin-1-yl and the like),

{circle around (4)} a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl and the like),

{circle around (5)} a C₃₋₈ cycloalkyl-carbonyl group optionallysubstituted by C₁₋₆ alkyl such as methyl, ethyl (e.g.,cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, 1-methyl-cyclohexylcarbonyl and the like),

{circle around (6)} a 5- to 7-membered aliphatic heterocyclic groupoptionally having 1 to 4 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom in addition to carbon atoms (e.g.,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl,3-piperidyl, (e.g, 4-piperidyl, 1-piperazinyl, 2-piperazinyl,3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl,thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl,hexahydroazepin-1-yl, etc.). This aliphatic heterocyclic group may besubstituted by C₁₋₆ alkyl (e.g., methyl, ethyl), C₁₋₆ alkyl-carbonyl(e.g., acetyl, propionyl) and the like.

{circle around (7)} a 5- to 7-membered aliphatic heterocyclic (e.g.,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl,3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl,4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino,2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl,etc.)-carbonyl group optionally having 1 to 4 hetero atoms selected froma nitrogen atom, an oxygen atom and a sulfur atom in addition to carbonatoms . This aliphatic heterocyclic-carbonyl group may be substituted byC₁₋₆ alkyl (e.g., methyl, ethyl), C₁₋₆ alkyl-carbonyl (e.g., acetyl,propionyl) and the like.

(4) a 5- to 7-membered aliphatic cyclic amino group which may containfurther 1 to 4 hetero atoms selected from a nitrogen atom, an oxygenatom and a sulfur atom in addition to carbon atoms and one nitrogen atom(e.g., 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and thelike). This aliphatic cyclic amino group may be substituted with C₁₋₆alkyl (e.g., methyl, ethyl), C₁₋₆ alkyl-carbonyl (e.g., acetyl,propionyl) and the like.

(5) a hydroxyl group,

(6) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy,butyryloxy and the like).

The “pyridyl group” represented by R² and R^(2a) may have, for example,1 to 5, preferably 1 to 3 of the above-mentioned substituents atsubstitutable positions, and when the number of substituents is 2 ormore, they may be the same or different. Further, an endocyclic nitrogenatom of the “pyridyl group” may be N-oxidized.

As the “pyridyl group” of the “pyridyl group having at the positionadjacent to a nitrogen atom of the pyridyl group a substituent includingno aromatic group” represented by R^(2a), 1-, 2-, 3- and 4-pyridyl groupare exemplified, and 4-pyridyl group is particularly preferable.

As the “aromatic group” of the “aromatic group optionally having asubstituent,” represented by R³ and R^(3a), an aromatic hydrocarbongroup, an aromatic heterocyclic group, etc. are exemplified.

As the “aromatic hydrocarbon group”, for example, a monocyclic or fusedpolycyclic (bicyclic or tricyclic) aromatic hydrocarbon group having 6to 14 carbon atoms are exemplified. As specific examples thereof, forexample, C₆₋₁₄ aryl such as phenyl, 1-naphthyl, 2-naphthyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like, etc.are exemplified.

As the “aromatic heterocyclic group”, for example, a 5- or 14-membered(preferably, 5- or 10-membered) monocyclic or bicyclic aromaticheterocyclic groups preferably containing 1 to 4 of 1 or 2 kinds ofhetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, are exemplified. Specifically, anaromatic heterocylic group such as, for example, 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pirazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isooxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl and the like, are exemplified.

As the “substituent” of the above-mentioned “aromatic group optionallyhaving a substituent”, for example, 1 to 5, preferably 1 to 3 of thesame moieties as for the “substituent” of the above-mentioned“hydrocarbon group optionally having a substituent” represented by R⁵are exemplified. When the number of the substituents is two or more,these substituents may be the same or different. Further, adjacent twosubstituents may form a 4- to 7-membered aliphatic carbon ring.Preferable is a 5- or 6-membered aliphatic carbon ring.

R³ and R³a preferably represent a C₆₋₁₄ aryl group, or a 5- to14-membered aromatic heterocyclic group preferably containing 1 to 4 of1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms. More preferably,they represent a phenyl group optionally having a substituent or athienyl group optionally having a substituent, and a phenyl groupoptionally having a substituent is particularly preferable.

As the substituent on the C₆₋₁₀ aryl group, a phenyl group, a 5- to14-membered aromatic heterocyclic group and a thienyl group, preferableare 1 to 3 substituents selected from a halogen atom, C₁₋₃alkylenedioxy, C₁₋₆ alkyl which may be halogenated, carboxy C₂₋₆alkenyl, C₃₋₈ cycloalkyl, C₁₋₈ alkoxy which may be halogenated, hydroxy,C₇₋₁₆ aralkyloxy, C₁₋₆ alkyl-carbonyloxy, carboxy, C₁₋₆ alkoxy-carbonyl,cyano, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl and particularly, a halogenatom, C₁₋₆ alkyl which may be halogenated (e.g., C₁₋₃ alkyl such asmethyl, ethyl, propyl and the like), C₁₋₈ alkoxy which may behalogenated (e.g., C₁₋₃ alkoxy such as methoxy, ethoxy and the like),carboxy, C₁₋₆ alkoxy-carbonyl, cyano, C₁₋₆ alkylthio (e.g., methylthio,ethylthio), C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl),etc. are preferable. Further, two alkyl groups adjacent as substituentsmay form a 5-membered aliphatic carbocyclic ring.

As the compound (Ibb), specifically, compounds represented by thefollowing formula are preferably used:

wherein R^(1b) represents (i) a hydrogen atom, (ii) a C₁₋₆ alkyl groupoptionally substituted by a substituent selected from the groupconsisting of a halogen atom, C₁₋₆ alkoxy-carbonyl, carboxy, cyano, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, hydroxy, C₁₋₆ alkoxyand C₁₋₆ alkyl-carbonyl, (iii) a C₆₋₁₄ aryl group optionally having asubstituent selected from the group consisting of a halogen atom and agroup represented by the formula: —S(O)_(n)—R^(1bb) (R^(1bb) representsa C₁₋₆ alkyl group, and n represents an integer of 0 to 2), (iv) a C₇₋₁₅aralkyl group, (v) an amino group optionally having one or twosubstituents selected from {circle around (1)} C₁₋₆ alkyl, {circlearound (2)} C₁₋₆ alkyl-carbonyl, {circle around (3)} ₁₋₆alkoxy-carbonyl, {circle around (4)} 5- to 7-memberedheterocyclic-carbonyl containing 1 to 4 hetero atoms selected from thegroup consisting of a nitrogen atom, an oxygen atom and a sulfur atom,in addition to carbon atoms, optionally substituted with a halogen atom,C₁₋₆ alkyl group or C₁₋₆ alkoxy, {circle around (5)} C₆₋₁₄aryl-carbamoyl, {circle around (6)} C₁₋₆ alkyl-carbamoyl which may behalogenated, {circle around (7)} C₁₋₁₆ alkoxy-carbonyl which may behalogenated, {circle around (8)} C₁₋₆ alkoxy-carbamoyl and {circlearound (9)} C₆₋₁₄ aryloxy-carbamoyl, (vi) a 5- to 10-membered aliphaticheterocyclic group containing 1 to 4 of 1 or 2 kinds of hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, optionally substituted by oxo, C₁₋₆ alkyl,C₆₋₁₄ aryl, C₁₋₆ alkyl-carbonyl or C₁₋₆ alkoxy-carbonyl, (vii) an acylgroup represented by the formula: —(C═O)—R^(5b) (wherein R^(5b)represents a hydrogen atom, a C₁₋₆ alkyl group which may be halogenatedor a C₆₋₁₄ aryl group which may be halogenated), or (viii) an acyl grouprepresented by the formula: —(C═O)—OR^(5c) (wherein R^(5c) represents ahydrogen atom or a C₁₋₆ alkyl group),

R^(2b) represents a pyridyl group (preferably, 4-pyridyl group and thispyridyl group may be N-oxidized.) having at the position adjacent to anitrogen atom of the pyridyl group a substituent selected from the group(particularly, consisting of (1) to (4)) consisting of

(1) a C₁₋₆ alkyl group (this C₁₋₆ alkyl group may be substituted by ahalogen atom, cyano, hydroxy, C₃₋₈ cycloalkyl or a 5- to 7-memberedaliphatic heterocyclic group containing hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom in addition to carbonatoms),

(2) a halogen atom,

(3) an amino group optionally having a substituent selected from thegroup consisting of the following {circle around (1)} to {circle around(1)};

{circle around (1)} C₁₋₆ alkyl group (this C₁₋₆ alkyl group may besubstituted by halogen atoms, cyano, hydroxy, C₃₋₈ cycloalkyl or 5- to7-membered aliphatic heterocyclic group having 1 to 4 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon atoms),

{circle around (2)} a C₃₋₈ cycloalkyl group,

{circle around (3)} a C₁₋₆ alkyl-carbonyl group (this C₁₋₆alkyl-carbonyl group may be substituted by halogen atoms, cyano,hydroxy, C₃₋₈ cycloalkyl or 5- to 7-membered aliphatic heterocyclicgroup having 1 to 4 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom in addition to carbon atoms),

{circle around (4)} a C₁₋₆ alkoxy-carbonyl group,

{circle around (5)} a C₃₋₈ cycloalkyl-carbonyl group optionallysubstituted by C₁₋₆ alkyl,

{circle around (6)} a 5- to 7-membered aliphatic heterocyclic grouphaving 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atomand a sulfur atom in addition to carbon atoms (this aliphaticheterocyclic group may be substituted by C₁₋₆ alkyl or C₁alkyl-carbonyl),

{circle around (7)} a 5- to 7-membered aliphatic heterocyclic-carbonylgroup having 1 to 4 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom in addition to carbon atoms (thisaliphatic heterocyclic-carbonyl group may be substituted by C₁₋₆ alkylor C₁₋₆ alkyl-carbonyl),

(4) a 5- to 7-membered aliphatic cyclic amino group optionally furthercontaining hetero atoms selected from a nitrogen atom, an oxygen atomand a sulfur atom in addition to carbon atoms and one nitrogen atom(this aliphatic cyclic amino group may be substituted by C₁₋₆ alkyl orC₁₋₆ alkyl-carbonyl),

(5) a hydroxy group, and

(6) a C₁₋₆ alkyl-carbonyloxy group, and

R^(3b) represents {circle around (1)} a C₆₋₁₄ aryl group or {circlearound (2)} a 5- to 14-membered aromatic heterocyclic group preferablycontaining 1 to 4 of 1 or 2 kinds of hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, which optionally has a substituent selected from the groupconsisting of C₁₋₁₆ alkyl which may be halogenated, C₁₋₆ alkoxy, ahalogen atom, carboxyl, C₁₋₆ alkoxy-carbonyl, cyano, C₁₋₆ alkylthio andC₁₋₆ alkylsulfonyl.

As the C₁₋₆ alkyl group represented by R^(1b), for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl, etc. are used, and particularly, a C₁₋₄ alkyl group suchas methyl, ethyl, propyl, butyl and the like are preferable, and a C₁₋₃alkyl group such as methyl, ethyl, propyl, etc. are particularlypreferable.

As the halogen atom which is a substituent of the C₁₋₆ alkyl grouprepresented by R^(1b), a fluorine atom, a chlorine atom, a bromine atomand an iodine atom and the like are used.

As the C₁₋₆ alkoxy-carbonyl which is a substituent of the C₁₋₆ alkylgroup represented by R^(1b), for example, methoxycarbonyl, ethoxycarbonyand the like are preferable.

As the C₁₋₆ alkylthio which is a substituent of the C₁₋₆ alkyl grouprepresented by R^(1b), for example, methylthio, ethylthio and the likeare preferable.

As the C₁₋₆ alkylsulfinyl which is a substituent of the C₁₋₆ alkyl grouprepresented by R^(1b), for example, methylsulfinyl, ethylsulfinyl andthe like are preferable.

As the C₁₋₆ alkylsulfonyl which is a substituent of the C₁₋₆ alkyl grouprepresented by R^(1b), for example, methylsulfonyl, ethylsulfonyl andthe like are preferable.

As the C₁₋₆ alkoxy which is a substituent of the C₁₋₆ alkyl grouprepresented by R^(1b), for example, methoxy, ethoxy, propoxy and thelike are preferable.

As the C₁₋₆ alkyl-carbonyl which is a substituent of the C₁₋₆ alkylgroup represented by R^(1b), for example, acetyl, propionyl and the likeare preferable.

As the C₁₋₆ alkyl group represented by R^(1bb), for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl, etc. are used, and particularly, a C₁₋₃ alkyl group suchas methyl, ethyl, propyl and the like are preferable, particularly,methyl is preferable.

As the C₆₋₁₄ aryl group represented by R^(1b), for example, phenyl,naphthyl, etc. are preferable, and of them, phenyl is particularlypreferable.

As the halogen atom which is a substituent of the C₆₋₁₄ aryl grouprepresented by R^(1b), a fluorine atom, a chlorine atom, a bromine atomand an iodine atom are used.

As the C₇₋₁₅ aralkyl group represented by R^(1b), for example, aphenyl-C₁₋₃ alkyl group such as benzyl, phenylethyl, phenylpropyl andthe like are preferable.

As the C₁₋₆ alkyl group which is a substituent of an amino grouprepresented by R^(1b), for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are used,and particularly, a C₁₋₃ alkyl group such as methyl, ethyl, propyl andthe like are preferable, particularly, methyl is preferable.

As the C₁₋₆ alkyl-carbonyl which is a substituent of an amino grouprepresented by R^(1b), for example, a C₁₋₃ alkyl-carbonyl group such asacetyl, propionyl and the like are preferable.

As the “5- to 7-membered heterocyclic-carbonyl containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygenatom and a sulfur atom, in addition to carbon atoms” which is asubstituent of an amino group represented by R^(1b), for example, a 5-to 7-membered heterocyclic (e.g., pyridyl and the like)-carbonyl groupcontaining 1 or 2 hetero atoms selected from the group consisting of anitrogen atom, an oxygen atom and a sulfur atom, etc. are preferable. Asthe substituent of the heterocyclic group of this heterocyclic-carbonylgroup, a halogen atom such as a chlorine atom, a C₁₋₆ alkyl group suchas methyl, ethyl and the like, and a C₁₋₆ alkoxy group such as methoxy,ethoxy and the like are preferable.

As the C₆₋₁₄ aryl-carbamoyl which is a substituent of an amino grouprepresented by R^(1b), for example, phenyl-carbamoyl, etc. arepreferable.

As the C₁₋₆ alkyl-carbamoyl which may be halogenated which is asubstituent of an amino group represented by R^(1b), for example,methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl optionally substitutedby a halogen atom (e.g., chlorine atom) and the like are preferable.

As the C₁₋₆ alkoxy-carbonyl which may be halogenated which is asubstituent of an amino group represented by R^(1b), for example,methoxycarbamoyl, ethoxycarbamoyl, propoxycarbamoyl optionallysubstituted by halogen atoms (e.g., chlorine atom) and the like arepreferable.

As the C₁₋₆ alkoxy-carbamoyl which is a substituent of an amino grouprepresented by R^(1b), for example, methoxycarbamoyl, ethoxycarbamoyl,propoxycarbamoyl and the like are preferable.

As the C₆₋₁₄ aryloxy-carbamoyl which is a substituent of an amino grouprepresented by R^(1b), for example, phenyloxycarbamoyl and the like arepreferable.

As the 5- to 10-membered aliphatic heterocyclic group represented byR^(1b), for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,3-oxazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl,morpholino, thiomorpholino and the like, are used, and of them,4-piperidyl, 1-piperazinyl, 3-oxazolidinyl, 1-imidazolidinyl and thelike are preferable.

As the 5- to 10-membered aliphatic heterocyclic group optionallysubstituted by oxo, C₁₋₆ alkyl (preferably, methyl, ethyl), C₆₋₁₄ aryl(preferably, phenyl), C₁₋₆ alkyl-carbonyl (preferably, acetyl,propionyl) or C₁₋₆ alkoxy-carbonyl (preferably, methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl) represented by R^(1b),1-methyl-4-piperidyl, 4-methyl-1-piperazinyl, 2-oxo-3-oxazolidinyl,2-oxo-1-imidazolidinyl, 2-oxo-3-phenyl-1-imidazolidinyl and the like arepreferable.

As R^(5b) of the formula: —(C═O)—R^(5b) represented by R^(1b), ahydrogen atom, a C₁₋₆ alkyl group which may be halogenated (methyl,ethyl, trifluoromethyl and the like), a C₆₋₁₄ alkyl group which may behalogenated (phenyl, naphthyl, fluorophenyl, chlorophenyl and the like),etc. are preferable.

As R^(5c) of the formula —(C═O)—OR^(5c) represented by R^(1b), ahydrogen atom, a C₁₋₃ alkyl group (methyl, ethyl, etc.), etc. arepreferable.

As R^(1b), a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) ispreferable, particularly, a C₁₋₃ alkyl group such as methyl, ethyl,propyl, etc. is preferable.

As specific examples of a substituent of the pyridyl group representedby R^(2b), 1 to 3, preferably 1 or 2 substituents selected from thefollowing (1) to (6), particularly (1) to (4) are used.

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, preferablya C₁₋₄ alkyl group such as methyl, ethyl, propyl, butyl and the like):this C₁₋₆ alkyl group may be substituted by a halogen atom, cyano,hydroxy, C₃₋₈ cycloalkyl or 5- to 7-membered aliphatic heterocyclicgroup containing hetero atoms selected from a nitrogen atom, an oxygenatom and a sulfur atom in addition to carbon atoms (e.g.,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl,3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl,4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino,2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and thelike),

(2) a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom,iodine atom),

(3) an amino group optionally having a substituent selected from thegroup consisting of the following {circle around (1)} to {circle around(7)}:

{circle around (1)} a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and thelike, preferably a C₁₋₃ alkyl group such as methyl, ethyl, propyl andthe like): this C₁₋₆ alkyl group may be substituted by a halogen atom,cyano, hydroxy, C₃₋₈ cycloalkyl or 5- to 7-membered aliphaticheterocyclic group optionally containing hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom in addition to carbonatoms (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl,3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl,thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl,hexahydroazepin-1-yl and the like),

{circle around (2)} a C₃₋₈ cycloalkyl group (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like),

{circle around (3)} a C₁₋₆ alkyl-carbonyl group (e.g., acetyl,propionyl, butylyl, valeryl, isovaleryl, 2-methylbutyryl, pivaloyl andthe like): this C₁₋₆ alkyl-carbonyl group maybe substituted by a halogenatom, cyano, hydroxy , C₃₋₈ cycloalkyl or 5- to 7-membered aliphaticheterocyclic group optionally containing hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom in addition to carbonatoms (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl,3-piperazinyl, 4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl,thiomorpholino, 2-thiomorpholinyl, 3-thiomorpholinyl,hexahydroazepin-1-yl and the like),

{circle around (4)} a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,ethoxy carbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl and the like),

{circle around (5)} a C₃₋₈ cycloalkyl-carbonyl group optionallysubstituted by C₁₋₆ alkyl such as methyl, ethyl (e.g.,cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, 1-methylcyclohexyl-carbonyl and the like),

{circle around (6)} a 5- to 7-membered aliphatic heterocyclic groupoptionally having 1 to 4 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom in addition to carbon atoms (e.g.,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl,3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl,4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino,2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and thelike). This aliphatic heterocyclic group may be substituted by C₁₋₆alkyl (e.g., methyl, ethyl) or C₁₋₆ alkyl-carbonyl (e.g., acety,propionyl),

{circle around (7)} a 5- to 7-membered aliphatic heterocyclic (e.g.,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl,3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl,4-piperazinyl, morpholino, 2-morpholinyl, 3-morpholinyl, thiomorpholino,2-thiomorpholinyl, 3-thiomorpholinyl, hexahydroazepin-1-yl and thelike)-carbonyl group having 1 to 4 hetero atoms selected from a nitrogenatom, an oxygen atom and a sulfur atom in addition to carbon atoms Thisheterocyclic-carbonyl group may be substituted by C₁₋₆ alkyl (e.g.,methyl, ethyl) or C₁₋₆ alkyl-carbonyl (e.g., acety, propionyl),

(4) a 5- or 7-membered aliphatic cyclic amino group which may containhetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom in addition to carbon atoms and one nitrogen atom (e.g.,1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and the like).This aliphatic cyclic amino group may be substituted with C₁₋₆ alkyl(e.g., methyl, ethyl), C₁₋₆ alkyl-carbonyl (e.g., acety, propionyl) andthe like;

(5) a hydroxyl group,

(6) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy,butyryloxy and the like).

Of them, as a substituent of the pyridyl group represented by R^(2b),for example, a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propionylamino, butylylamino, valerylamino, isovalerylamino,2-methylbutyrylamino, pivaloylamino and the like) is preferable, andparticularly, a C₁₋₃ alkyl-carbonylamino group such as acetyl,propionylamino, etc. is preferable.

As the C₆₋₁₄ aryl group represented by R^(3b), for example, phenyl,naphthyl, etc. are preferable, and of them, phenyl is particularlypreferable.

As the 5- to 14-membered aromatic heterocyclic group preferablycontaining 1 to 4 of 1 or 2 kinds of hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms, represented by R^(3b), for example, a 5- or 6-membered aromaticheterocyclic group preferably containing 1 to 4 of 1 or 2 kinds ofhetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, such as thienyl and the like, arepreferable.

As the C₁₋₆ alkyl group which may be halogenated, which is a substituentof the C₆₋₁₄ aryl group or the aromatic heterocyclic group, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, etc. which may be substituted by a halogenatom (e.g., fluorine, chlorine and the like) are used, and particularly,a C₁₋₃ alkyl group which may be halogenated such as methyl, ethyl,propyl, trifluoromethyl and the like are preferable.

As the C₁₋₆ alkoxy which is a substituent of the C₆₋₁₄ aryl group or thearomatic heterocyclic group, for example, methoxy, ethoxy, propoxy, etc.are used, and of them, methoxy is particularly preferable.

As the halogen atom which is a substituent of the C₆₋₁₄ aryl group orthe aromatic heterocyclic group, a fluorine atom, a chlorine atom, abromine atom and an iodine atom are used, and of them, a fluorine atomand a chlorine atom, etc. are preferable.

As the C₁₋₆ alkoxy-carbonyl which is a substituent of the C₆₋₁₄ arylgroup or the aromatic heterocyclic group, for example, methoxycarbonyl,ethoxycarbonyl and the like are preferable.

As the C₁₋₆ alkylthio which is a substituent of the C₆₋₁₄ aryl group orthe aromatic heterocyclic group, for example, methylthio, ethylthio andthe like are preferable.

As the C₁₋₆ alkylsulfonyl which is a substituent of the C₆₋₁₄ aryl groupor the aromatic heterocyclic group, for example, methylsulfonyl,ethylsulfonyl and the like are preferable.

As R^(3b), a C₆₋₁₄ aryl group optionally having a substituent selectedfrom the group consisting of C₁₋₆ alkyl and a halogen atom ispreferable, and a phenyl group optionally substituted by methyl or achlorine atom is more preferable.

As the compound (Ibbb), for example,

(1) the compound (Ibbb) wherein R^(1b) is a C₁₋₆ alkyl group optionallyhaving a substituent selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl and C₁₋₆alkylsulfonyl, R^(2b) is a C₁₋₆ alkyl-carbonylamino group or a C₃₋₈cycloalkylamino group, R^(3b) is a C₆₋₁₄ aryl group optionally having asubstituent selected from the group consisting of C₁₋₆ alkyl and ahalogen atom,

(2) the compound (Ibbb) wherein R^(1b) is a C₁₋₃ alkyl group optionallyhaving a substituent selected from the group consisting of a halogenatom, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl and C₁₋₆alkylsulfonyl, R^(2b) is a C₁₋₃ alkyl-carbonylamino group or a C₃₋₈cycloalkylamino group, R^(3b) is a phenyl group optionally having asubstituent selected from the group consisting of methyl or a chlorineatom, and the like are preferable.

As preferable specific examples of the compound (Ibbb), compoundsproduced in Examples 1 to 113 described later are exemplified, and ofthem,5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-4-(3-methylphenyl)-1,3-thiazol(Example 3),[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine(Example 7-4),2-ethyl-5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole (Example11),5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole(Example 15),4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole(Example 16-1),4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (Example22),N-[4-[2-ethyl-4-(3-methylphenyl)-1-1,3-thiazol-5-yl]-2-pyridyl]acetamide(Example 29-2),N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide(Example 29-4),N-[4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide(Example 30-1),N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide(Example 30-2),N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide(Example 30-3),N-[4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2pyridyl]propionamide(Example 30-7),N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide(Example 30-8),N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide(Example 30-9),N-cyclohexyl-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine(Example 36-4),N-cyclohexyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine(Example 36-5),N-cyclopentyl-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5yl]-2-pyridylamine(Example 36-6),N-cyclopentyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine(Example 36-7),4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclohexyl-2-pyridylamine(Example 36-10),4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclopentyl-2-pyridylamine(Example 36-11),N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]acetamide(Example 39),N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotimide(Example 42-1),6-chloro-N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide(Example 44-3),N-[4-(3,5-dimethylphenyl)-5-(2methyl-4-pyridyl)-1,3-thiazol-2-yl]-6methylnicotinamide(Example 46-3),N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-6-methoxynicotinamide(Example 48-3),4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-(4-methylsulfinylphenyl)-1,3-thiazole(Example 54),4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole(Example 57),5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole(Example 58-4),N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide(Example 58-6),N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl-]-2-pyridyl]propionamide(Example 58-7),N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]pivalamide(Example 58-8) and the like are preferable.

As a salt of the compound (Ia), (Ib) or (Ic), for example, metal salts,ammonium salts, salts with organic bases, salts with inorganic acids,salts with organic acids, salts with basic or acidic amino acids, etc.are exemplified. As suitable examples of metal salts, for example,alkali metal salts such as sodium salts, potassium salts and the like;alkaline earth metal salts such as potassium salts, magnesium salts,barium salts and the like; aluminum salts; etc. are exemplified. Assuitable examples of salts with organic bases, for example, salts withtrimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamin, cyclohexylamine,dicyclohexyamine, N,N′-dibenzylethylenediamine, etc. are exemplified. Assuitable examples of salts with inorganic acids, for example, salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, etc. are exemplified. As suitable examples of saltswith organic acids, for example, salts with formic acid, acetic acid,trifluroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.are exemplified. As suitable examples of salts with basic amino acids,for example, salts with arginine, lysine, ornithine, etc. areexemplified, and as suitable examples of salts with acidic amino acids,for example, salts with aspartic acid, glutamic acid, etc. areexemplified.

Of them, pharmaceutically acceptable salts are preferable. When anacidic functional group is contained in a compound, for example,inorganic salts such as alkali metal salts (e.g., sodium salts,potassium salts and the like), alkaline earth metal salts (e.g., calciumsalts, magnesium salts, barium salts and the like), and ammonium salts,etc. are exemplified, and when a basic functional group is contained ina compound, for example, salts with inorganic acids such as hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,etc. or salts with organic acids such as acetic acid, phthalic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. arepreferable.

A pro-drug of the compound (Ia), compound (Ib), compound (Ic), compound(Iaa), compound (Ibb) or a salt thereof of the present invention(hereinafter, sometimes referred to as compound (I) of the presentinvention) means a compound which is converted into the compound (I) ofthe present invention by reactions of enzymes, gastric acid and the likeunder physiological conditions in organisms, namely, a compound whichcauses enzymatic oxidation, reduction, hydrolysis and the like to beconverted into the compound (I) of the present invention, and a compoundwhich causes hydrolysis and the like by gastric acid, etc. to beconverted into a compound (I) of the present invention.

As the pro-drug of the compound (I) of the present invention, compoundsobtained by acylation, alkylation and phosphorylation of an amino groupof the compound (I) of the present invention (e.g., compounds obtainedby eicosanoylation, alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4yl)-methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation,tertbutylation of an amino group of the compound (I) of the presentinvention, etc.); compounds obtained by acylation, alkylation,phosphorylation and boration of a hydroxyl group of the compound (I) ofthe present invention (e.g., compounds obtained by acetylation,palmitoylation, propanoylation, pivaloylation, succinylation,fumarylation, alanylation, dimethylaminomethylcarbonylation of ahydroxyl group of the compound (I) of the present invention, etc.);compounds obtained by esterification and amidation of a carboxyl groupof the compound (I) of the present invention (e.g., compounds obtainedby ethylesterification, phenylesterification,carboxymethylesterification, dimethylaminomethylesterification,pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification,phthalidylesterification,(5-methyl-2-oxo-1,3-dioxolene-4-yl)methylesterification,cyclohexyloxycarbonylethylesterification, methylamidation of a carboxylgroup of the compound (I) of the present invention, etc.), etc. areexemplified. These compounds can be produced from the compound (I) ofthe present invention according to methods known per se.

Further, a prodrug of the compound (I) of the present invention may alsobe one which is converted into the compound (I) of the present inventionunder physiological conditions as described in “Iyakuhin no Kaihatsu”,vol. 7, Bunshi Sekkei, pp. 163to 198, Hirokawa Shoten, 1990.

A method for producing the compound (Ia), (Ib), (Ic) or a salt thereofof the present invention will be illustrated below. Hereinafter, thecompound (I) means a compound including compounds (Ia), (Ib), (Ic),(Ibb) and (Ibbb).

The compound (I) of the present invention is obtained by a methodrepresented by the following reaction formula 1 or methods according tothis method, and additionally, obtained, for example, by methodsdescribed in JP-A No. 60-58981, JP-A No. 61-10580, JP-T No. 7-503023, WO93/15071, DE-A-3601411, JP-A No. 5-70446 and methods according to them.

Symbols of compounds in the following reaction formulae 1 to 2 are asdefined above. Compounds in the reaction formulae also include salts,and as this salt, for example, the same salts as for the compound (Ia)are exemplified.

When compounds (II), (III), (V), (VII), (XI), (XIII) and (XIV) arecommercially available, they may be used without any treatment, and alsocan be produced by methods known per se or methods according to them.

The compound (IV) is obtained by condensing a compound (II) with acompound (III) in the presence of a base.

In the compound (III), R⁸ represents, for example, {circle around (1)} aC₁₋₆ alkoxy (e.g., methoxy, ethoxy and the like), {circle around (2)} adi-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino and the like),{circle around (3)} an N—C₆₋₁₀ aryl-N—C₁₋₆ alkylamino (e.g.,N-phenyl-N-methylamino and the like), {circle around (4)} a 3- to7-membered cyclic amino optionally substituted with a C₆₋₁₀ aryl and(or) C₁₋₆ alkyl (e.g., pyrrolidin-1-yl, morpholino, methylaziridin-1-yl,and the like), etc.

The amount of the compound (III) used is about 0.5 to about 3.0 mol,preferably about 0.8 to about 2.0 mol per mol of the compound (II).

The amount of a base used is about 1.0 to about 30 mol, preferably about1.0 to about 10 mol per mol of the compound (II).

As the “base”, for example, basic salts such as sodium carbonate,potassium carbonate, cesium carbonate and the like, inorganic bases suchas sodium hydroxide, potassium hydroxide and the like, aromatic aminessuch as pyridine, lutidine and the like, tertiary amines suchtriethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like, alkali metalhydrides such as sodium hydride, potassium hydride and the like, metalamides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide and the like, metal alkoxides such as sodiummethoxide, sodium ethoxide, potassium tert-butoxide and the like, etc.are exemplified.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, ethers, amides, alcohols, water or mixtures of two or moreof them, etc. are used.

The reaction temperature is usually from about −5° C. to about 200° C.,preferably from about 5° C. to about 150° C. The reaction time isusually from about 5 minutes to about 72 hours, preferably from about0.5 to about 30 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

A compound (VIII) is obtained by treating a compound (IV) with an acid.

The amount of an acid used is about 1.0 to about 100 mol, preferablyabout 1.0 to about 30 mol per mol of the compound (IV).

As the “acid”, for example, mineral acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, etc. are used.

The present reaction is conducted in the presence of a solvent inactiveto the reaction. The solvent is not particularly restricted providingthe reaction can progress, and for example, water, mixtures of waterwith amides, mixtures of water with alcohols, etc. are used.

The reaction temperature is usually from about 20° C. to about 200° C.,preferably from about 60° C. to about 150° C. The reaction time isusually from about 30 minutes to about 72 hours, preferably from about 1hour to about 30 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

A compound (VIII) can also be obtained by condensing a compound (VII)with a compound (VI) obtained by treating a compound (V) with a base.

In the compound (VI), M represents, for example, an alkali metal such aslithium, sodium, potassium and the like.

In the compound (VII), as R⁹, for example, the same moieties as for R⁸are exemplified.

The amount of a base used is about 1.0 to about 30 mol, preferably about1.0 to about 10 mol per mol of the compound (V).

As the “base”, for example, metal amides such as sodium amide, lithiumdiisopropylamide, lithium hexamethyldisilazide and the like, and alkylmetal compounds such as alkyllithium and the like are used.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, ormixtures of two or more of them, etc. are used.

The reaction temperature is usually from about −78° C. to about 60° C.,preferably from about −78° C. to about 20° C. The reaction time isusually from about 5 minutes to about 24 hours, preferably from about0.5 to about 3 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

A compound (IX) is obtained by treating a compound (VIII) with halogens.This reaction is conducted in the presence of a base or basic salt, ifnecessary.

In the compound (IX), Hal represents halogens.

The amount of halogens used is about 1.0 to about 5.0 mol, preferablyabout 1.0 to about 2.0 mol per mol of the compound (VIII).

As the “halogens”, bromine, chlorine, iodine, etc. are exemplified.

The amount of a base used is about 1.0 to about 10.0 mol, preferablyabout 1.0 to about 3.0 mol per mol of the compound (VIII).

As the “base”, for example, aromatic amines such as pyridine, lutidineand the like, tertiary amines such triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine and the like, etc. are exemplified.

The amount of a basic salt used is about 1.0 to about 10.0 mol,preferably about 1.0 to about 3.0 mol per mol of the compound (VIII).

As the “basic salt”, for example, sodium carbonate, potassium carbonate,cesium carbonate, sodium hydrogen carbonate, sodium acetate, potassiumacetate, etc. are exemplified.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides,halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromaticamines, or mixtures of two or more of them, etc. are used.

The reaction temperature is usually from about −20° C. to about 150° C.,preferably from about 0° C. to about 100° C. The reaction time isusually from about 5 minutes to about 24 hours, preferably from about 10minutes to about 5 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

A compound (I) can be obtained by condensing a compound (IX) with acompound (X). The present reaction is conducted in the presence of abase, if necessary.

When the compound (X) is commercially available, it may be used withoutany treatment, and also can be obtained by methods known per se ormethods according to them, further, can be obtained by a method of thefollowing reaction formula 2, etc.

The amount of the compound (X) used is about 0.5 to about 3.0 mol,preferably about 0.8 to about 2.0 mol per mol of the compound (IX).

The amount of a base used is about 1.0 to about 30 mol, preferably about1.0 to about 10 mol per mol of the compound (IX).

As the “base”, for example, basic salts such as sodium carbonate,potassium carbonate, cesium carbonate, sodium hydrogen carbonate and thelike, aromatic amines such as pyridine, lutidine and the like, tertiaryamines such triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and thelike, etc. are exemplified.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, ethers, amides, alcohols, nitrites, or mixtures of two ormore of them, etc. are used.

The reaction temperature is from about −5° C. to about 200° C.,preferably from about 5° C. to about 150° C. The reaction time isusually from about 5 minutes to about 72 hours, preferably from about0.5 to about 30 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

A compound (XII) can be obtained by condensing a compound (XI) withamines represented by R¹H.

In the compound (XI), R¹⁰ represents an aromatic hydrocarbon group oralkoxy. As the “aromatic hydrocarbon group”, a phenyl group optionallyhaving a substituent, etc. are listed. As the “alkoxy”, for example,C₁₋₆ alkoxys such as methoxy, ethoxy, propoxy, isopropoxy, butoxy andthe like, etc. are exemplified.

The amount of the “amines” used is about 1.0 to about 30 mol, preferablyabout 1.0 to about 10 mol per mol of the compound (XI).

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, ethers, amides, alcohols, nitrites, ketones, or mixturesof two or more of them, etc. are used.

The reaction temperature is from about −5° C. to about 200° C.,preferably from about 5° C. to about 120° C. The reaction time isusually from about 5 minutes to about 72 hours, preferably from about0.5 to about 30 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

A compound (X) can be obtained by hydrolyzing the compound (XII) with anacid or base.

The amount of the acid or base used is about 0.1 to about 50 mol,preferably about 1 to about 20 mol, respectively, per mole of thecompound (XII).

As the “acid”, for example, mineral acids such as hydrochloric acid,hydrobromic acid, sulfuric acid and the like, Lewis acids such as borontrichloride, boron tribromide and the like, co-use of Lewis acids withthiols or sulfides, and organic acids such as trifluoroacetic acid,p-toluenesulfonic acid and the like, etc. are used.

As the “base”, for example, metal hydroxides such as sodium hydroxide,potassium hydroxide, barium hydroxide and the like, basic salts such assodium carbonate, potassium carbonate and the like, metal alkoxides suchas sodium methoxide, sodium ethoxide, potassium tert-butoxide and thelike, organic bases such as triethylamine, imidazole, formamidine andthe like, etc. are used.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, alcohols, ethers, aromatic hydrocarbons, aliphatichydrocarbons, halogenated hydrocarbons, sulfoxides, water or mixtures oftwo or more of them, etc. are used.

The reaction time is usually from about 10 minutes to about 50 hours,preferably from about 30 minutes to about 12 hours. The reactiontemperature is usually from about 0° C. to about 200° C., preferablyfrom about 20° C. to about 120° C.

A compound (X) can also be obtained by treating a compound (XIII) withhydrogen sulfide in the presence of a base.

The amount of hydrogen sulfide used is about 1 to about 30 mol per molof the compound (XIII).

The amount of a base used is about 1.0 to about 30 mol, preferably about1.0 to about 10 mol per mol of the compound (XIII).

As the “base”, for example, aromatic amines such as pyridine, lutidineand the like, tertiary amines such triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine and the like, etc. are used.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, ethers, aromatic amines, or mixtures of two or more ofthem, etc. are used.

The present reaction is effected under normal pressure or positivepressure. The reaction temperature is usually from about −20° C. toabout 80° C., preferably from about −10° C. to about 30° C. The reactiontime is usually from about 5 minutes to about 72 hours, preferably fromabout 0.5 to about 30 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

A compound (X) can also be obtained by treating a compound (XIII) withdithiophosphoric acid 0,0-diethyl ester in the presence of an acid.

The amount of dithiophosphoric acid 0,0-diethyl ester used is about 0.9to about 2 mol per mole of the compound (XIII).

The amount of an acid used is about 3.0 to about 30 mol, preferablyabout 3.0 to about 10 mol per mol of the compound (XIII).

As the “acid”, for example, hydrogen halides such as hydrogen chloride,hydrogen bromide and the like, and mineral acids such as hydrochloricacid, hydrobromic acid and the like, etc. are exemplified.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, halogenated hydrocarbons, alcohols, amides, ethers, esters,water, or mixtures of two or more of them, etc. are used.

The reaction temperature is usually from about 0° C. to about 80° C.,preferably from about 0° C. to about 30° C. The reaction time is usuallyfrom about 5 minutes to about 72 hours, preferably from about 0.5 hoursto about 30 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

A compound (X) can also be obtained by treating a compound (XIV) withphosphorus pentasulfide or a Lawesson's reagent.

The amount of the phosphorus pentasulfide or Lawesson's reagent used isabout 0.5 to about 10 mol, preferably about 0.5 to about 3 mol per moleof the compound (XIV).

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, ethers, aromatic hydrocarbons, aliphatic hydrocarbons,halogenated hydrocarbons, or mixtures of two or more of them, etc. areused.

The reaction time is usually from about 10 minutes to about 50 hours,preferably from about 30 minutes to about 12 hours. The reactiontemperature is usually from about 0° C. to about 150° C., preferablyfrom about 20° C. to about 120° C.

The product (X) can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

When the compound (I) is an acylamino compound, the corresponding aminecan be subjected to an acylation reaction known per se to obtain theintended substance.

For example, of compounds (I), that in which a substituent at the2-position of a thiazole ring is acyamino optionally having asubstituent is obtained by reacting the corresponding 2-thiazolamine andacylating agent, if necessary in the presence of a base or acid.

The amount of the acylating agent used is about 1.0 to about 5.0 mol,preferably about 1.0 to about 2.0 mol per mol of the corresponding2-thiazolamine.

As the “acylating agent”, for example, carboxylic acids corresponding tothe acyl group of the intended substance, or reactive derivativesthereof (e.g., acid halide, acid anhydride, ester and the like), etc.are exemplified.

The amount of a base or acid used is about 0.8 to about 5.0 mol,preferably about 1.0 to about 2.0 mol per mol of the corresponding2-thiazolamine.

As the “base”, for example, triethylamine, pyridine,4-dimethylaminopyridine, etc. are exemplified.

As the “acid”, for example, methanesulfonic acid, p-toluenesulfonicacid, camphor-sulfonic acid, etc. are exemplified.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides,halogenated hydrocarbons, nitriles, sulfoxides, aromatic amines, ormixtures of two or more of them, etc. are used.

The reaction temperature is from about −20° C. to about 150° C.,preferably from about 0° C. to about 100° C. The reaction time isusually from about 5 minutes to about 24 hours, preferably from about 10minutes to about 5 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

Further, of compounds (I), that in which a substituent at the 5-positionof a thiazole ring is acylaminopyridyl optionaly having a substituent isobtained by reacting the corresponding 5-(2-aminopyridyl)thiazole andacylating agent, if necessary in the presence of a base or acid.

The amount of the acylation agent used is from about 1.0 to about 5.0mol, preferably from about 1.0 to about 2.0 mol per mol of thecorresponding 5-(2-aminopyridyl)thiazole.

As the “acylating agent”, for example, carboxylic acids corresponding tothe acyl group of the intended substance, or reactive derivativesthereof (e.g., acid halide, acid anhydride, ester and the like), etc.are exemplified.

The amount of a base or acid used is from about 0.8 to about 5.0 mol,preferably from about 1.0 to about 2.0 mol per mol of the corresponding5-(2-aminopyridyl)thiazole.

As the “base”, for example, triethylamine, pyridine,4-dimethylaminopyridine, etc. are exemplified.

As the “acid”, for example, methanesulfonic acid, p-toluenesulfonicacid, camphor-sulfonic acid, etc. are exemplified.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides,halogenated hydrocarbons, nitrites, sulfoxides, aromatic amines, ormixtures of two or more of them, etc. are used.

The reaction temperature is from about −20° C. to about 150° C.,preferably from about 0° C. to about 100° C. The reaction time isusually from about 5 minutes to about 24 hours, preferably from about 10minutes to about 5 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

Of compounds (I), that in which a substituent at the 5-position of athiazole ring is alkylaminopyridyl optionally having a substituent isobtained by reducing the corresponding acylaminopyridine with a reducingagent.

The amount of the reducing agent used is from about 1.0 to about 5.0mol, preferably from about 1.0 to about 3.0 mol per mol of thecorresponding acylaminopyridine.

As the “reducing agent”, for example, metal hydrides such as aluminumhydride, diisobutylaluminum hydride and the like, metal hydrogen complexcompounds such as lithium aluminum hydride, sodium boron hydride and thelike, borane complexes such as borane tetrahydrofuran complex, boranedimethylsulfide complex and the like, alkyl boranes such as thexylborane, dicyamyl borane and the like, etc. are exemplified.

In the present reaction, an acid is also added together with a reducingagent, if necessary.

The amount of an acid used is from about 0.8 to about 5.0 mol,preferably from about 1.0 to about 3.0 mol per mol of the correspondingacylaminopyridine.

As the “acid”, for example, Lewis acids such as aluminum chloride andthe like, are exemplified.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, ethers, aromatic hydrocarbons, aliphatic hydrocarbons,halogenated hydrocarbons, or mixtures of two or more of them, etc. areused.

The reaction temperature is from about −78° C. to about 150° C.,preferably from about 0° C. to about 100° C. The reaction time isusually from about 5 minutes to about 24 hours, preferably from about 10minutes to about 5 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

Of compounds (I), that in which a substituent at the 5-position of athiazole ring is alkylaminopyridyl optionally having a substituent isobtained by condensing the corresponding 5-(2-halogenopyridyl)thiazolewith amines.

The amount of the amine used is from about 1.0 to about 100.0 mol,preferably from about 1.0 to about 20.0 mol per mol of the corresponding5-(2-halogenopyridyl)thiazole.

As the halogen of the “5-(2-halogenopyridyl)thiazole”, fluorine,chlorine, bromine, iodine, etc. are exemplified.

As the “amines”, for example, aliphatic amines and cyclic aminescorresponding to the intended alkylamine, etc. are exemplified.

The present reaction is conducted, if necessary in the presence of abase or basic salt.

The amount of the base used is from about 1.0 to about 10.0 mol,preferably from about 1.0 to about 3.0 mol per mol of the corresponding5-(2-halogenopyridyl)thiazole.

As the “base”, for example, aromatic amines such as pyridine, lutidineand the like, tertiary amines such triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine and the like, etc. are used.

The amount of the basic salt used is from about 1.0 to about 10.0 mol,preferably from about 1.0 to about 3.0 mol per mol of the corresponding5-(2-halogenopyridyl)thiazole.

As the “basic salt”, for example, sodium carbonate, potassium carbonate,cesium carbonate, sodium hydrogen carbonate, sodium acetate, potassiumacetate, etc. are used.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides,halogenated hydrocarbons, nitrites, water or mixtures of two or more ofthem, etc. are used.

The reaction temperature is from about 0° C. to about 300° C.,preferably from about 20° C. to about 200° C. The reaction time isusually from about 5 minutes to about 48 hours, preferably from about 10minutes to about 15 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

When the compound (I) is an N-oxide, it is obtained by treating thecorresponding pyridyl compound with an organic peracid.

The amount of the organic peracid used is from about 0.8 to about 10mol, preferably from about 1.0 to about 3.0 mol per mol of thecorresponding pyridyl compound.

As the above-mentioned “organic peracid”, for example, peracetic acid,pertrifluoroacetic acid, m-chloroperbenzoic acid, etc. are exemplified.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols,nitriles, ketones or mixtures of two or more of them, etc. are used.

The reaction temperature is from about −20° C. to about 130° C.,preferably from about 0° C. to about 100° C. The reaction time isusually from about 5 minutes to about 72 hours, preferably from about0.5 to about 12 hours.

Further, an N-oxide can also be obtained by treating the correspondingpyridyl compound with hydrogen peroxide or alkyl hydroperoxide, ifnecessary in the presence of a base, acid or metal oxide.

The amount of the hydrogen peroxide or alkyl hydroperoxide used is fromabout 0.8 to about 10 mol, preferably from about 1.0 to about 3.0 molper mol of the corresponding pyridyl compound.

As the above-mentioned “alkyl hydroperoxide”, for example,tert-butylhydroperoxide, cumene hydroperoxide, etc. are exemplified.

The amount of the base, acid or metal oxide used is from about 0.1 toabout 30 mol, preferably from about 0.8 to about 5 mol per mol of thecorresponding pyridyl compound.

As the above-mentioned “base”, for example, inorganic bases such assodium hydroxide, potassium hydroxide and the like, basic salts such assodium carbonate, potassium carbonate and the like, etc. areexemplified.

As the above-mentioned “acid”, for example, mineral acids such ashydrochloric acid, sulfuric acid, perchloric acid and the like, Lewisacids such as boron trifluoride, aluminum chloride, titaniumtetrachloride and the like, organic acids such as formic acid, aceticacid and the like, etc. are exemplified.

As the above-mentioned “metal oxide”, for example, vanadium oxide(V₂O₅), osmium tetraoxide (OsO₄), tungsten oxide (WO₃), molybdenum oxide(MoO₃), selenium dioxide. (SeO₂), chromium oxide (CrO₃), etc. areexemplified.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols,nitrites, ketones or mixtures of two or more of them, etc. are used.

The reaction temperature is from about −20° C. to about 130° C.,preferably from about 0° C. to about 100° C. The reaction time isusually from about 5 minutes to about 72 hours, preferably from about0.5 to about 12 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

When the compound (I) is an S-oxide, it is obtained by treating thecorresponding sulfide with a peroxide.

The amount of the peroxide used is from about 0.8 to about 10 mol,preferably from about 1.0 to about 3.0 mol per mol of the correspondingsulfide.

As the above-mentioned “peracid”, for example, peracetic acid,pertrifluoroacetic acid, m-chloroperbenzoic acid, potassium persulfate,meta-periodic acid, etc. are exemplified.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols,nitrites, ketones or mixtures of two or more of them, etc. are used.

The reaction temperature is from about −20° C. to about 130° C.,preferably from about 0° C. to about 100° C. The reaction time isusually from about 5 minutes to about 72 hours, preferably from about0.5 to about 12 hours.

Further, an S-oxide can also be obtained by treating the correspondingsulfide with hydrogen peroxide or alkyl hydroperoxide, if necessary inthe presence of a base, acid or metal oxide.

The amount of the hydrogen peroxide or alkyl hydroperoxide used is fromabout 0.8 to about 10 mol, preferably from about 1.0 to about 3.0 molper mol of the corresponding sulfide.

As the above-mentioned “alkyl hydroperoxide”, for example,tert-butylhydroperoxide, cumene hydroperoxide, etc. are exemplified.

The amount of the “base, acid or metal oxide” used is from about 0.1 toabout 30 mol, preferably from about 0.8 to about 5 mol per mol of thecorresponding sulfide.

As the above-mentioned “base”, for example, inorganic bases such assodium hydroxide, potassium hydroxide and the like, basic salts such assodium carbonate, potassium carbonate and the like, etc. areexemplified.

As the above-mentioned “acid”, for example, mineral acids such ashydrochloric acid, sulfuric acid, perchloric acid and the like, Lewisacids such as boron trifluoride, aluminum chloride, titaniumtetrachloride and the like, organic acids such as formic acid aceticacid and the like, etc. are exemplified.

As the above-mentioned “metal oxide”, for example, vanadium oxide(V₂O₅), osmium tetraoxide (OsO₄), tungsten oxide (WO₃), molybdenum oxide(MoO₃), selenium dioxide (SeO₂), chromium oxide (CrO₃), etc. areexemplified.

The present reaction is advantageously conducted in the absence orpresence of a solvent inactive to the reaction. This solvent is notparticularly restricted providing the reaction can progress, and forexample, halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols,nitriles, ketones or mixtures of two or more of them, etc. are used.

The reaction temperature is from about −20° C. to about 130° C.,preferably from about 0° C. to about 100° C. The reaction time isusually from about 5 minutes to about 72 hours, preferably from about0.5 to about 12 hours.

The product can be used in the following reaction as the reactionsolution itself or as a crude product, and can also be isolated from thereaction mixture according to an ordinary method, and can be easilypurified by separation means such as recrystallization, distillation,chromatography and the like.

In the above-mentioned reactions, when a starting material has amino,carboxy, hydroxy as a substituent, a protective group as generally usedmay be introduced into these groups by peptide chemistry and the like,and the intended compound can be obtained by removing the protectivegroup after the reaction, if necessary.

As the protective group for amino, for example, formyl or, C₁₋₆alkyl-carbonyls (e.g., acetyl, propionyl and the like), phenylcarbonyl,C₁₋₆ alkoxy-carbonyls (e.g. methoxycarbony, ethoxycarbonyl and thelike), phenyloxycarbonyl, C₇₋₁₀ aralkyloxy-carbonyls (e.g.,benzyloxycarbonyl and the like), trityl, phthaloyl, each optionallyhaving a substituent, etc. are used. As these substituents, halogenatoms (e.g., fluorine, chlorine, bromine, iodine and the like), C₁₋₆alkyl-carbonyls (e.g., acetyl, propionyl, valeryl and the like), nitro,etc. are used, and the number of the substituent is 1 to 3.

As the protective group for carboxy, for example, C₁₋₆ alkyls(e.g.,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like),phenyl, trityl, silyl, each optionally having a substituent, etc. areused. As these substituents, halogen atoms (e.g., fluorine, chlorine,bromine, iodine and the like), formyl, C₁₋₆ alkyl-carbonyls (e.g.,acetyl, propionyl, butylcarbonyl and the like), nitro, C₁₋₆ alkyls(e.g., methyl, ethyl, tert-butyl and the like), C₆₋₁₀ aryls (e.g.,phenyl, naphthyl and the like), etc. are used, and the number of thesubstituent is 1 to 3.

As the protective group for hydroxy, for example, C₁₋₆ alkyls (e.g.,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like),phenyl, C₇₋₁₁ aralkyls (e.g., benzyl and the like), formyl, C₁₋₆alkyl-carbonyls (e.g., acetyl, propionyl and the like),phenyloxycarbonyl, C₇₋₁₁ aralkyloxy-carbonyls (e.g., benzyloxycarbonyland the like), tetrahydropyranyl, tetrahydrofuranyl, and silyl, eachoptionally having a substituent, and so on are used. As thesesubstituents, halogen atoms (e.g., fluorine, chlorine, bromine, iodineand the like), C₁₋₆ alkyls (e.g. methyl, ethyl, tert-butyl and thelike), C₇₋₁₁ aralkyls (e.g., benzyl and the like), C₆₋₁₀ aryls (e.g.,phenyl, naphthyl and the like), nitro, etc. are used, and the number ofthe substituent is 1 to 4.

For removing a protective group, method known per se or methodsaccording to them are used, and for example, methods for treating withan acid, a base, ultraviolet ray, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetateand the like, or reducing methods are used.

In any case, further if necessary, the compound (I) can be synthesizedby using known de-protection reactions, acylation reactions, alkylationreactions, hydrogenation reactions, oxidation reactions, reductionreactions, carbon chain extension reactions, substituent interchangereactions, each alone or in combination of two or more of them. As thesereactions, for example, methods described in Shin Jikken Kagaku Koza 14,15, 1977 (Maruzen), etc. are adopted.

As the above-mentioned “alcohols”, for example, methanol, ethanol,propanol, isopropanol, tert-butanol, etc. are exemplified.

As the above-mentioned “ethers”, for example, diethyl ether, diisopropylether, diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,etc. are exemplified.

As the above-mentioned “halogenated hydrocarbons”, for example,dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride,etc. are exemplified.

As the above-mentioned “aliphatic hydrocarbons”, for example, hexane,pentane, cyclohexane, etc. are exemplified.

As the above-mentioned “aromatic hydrocarbons”, for example, benzene,toluene, xylene, chlorobenzene, etc. are exemplified.

As the above-mentioned “aromatic amines”, for example, pyridine,lutidine, quinoline, etc. are exemplified.

As the above-mentioned “amides”, for example, N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide, etc. areexemplified.

As the above-mentioned “ketones”, for example, acetone, methyl ethylketone, etc. are exemplified.

As the above-mentioned “sulfoxides”, for example, dimethylsulfoxide,etc. are exemplified.

As the above-mentioned “nitriles”, for example, acetonitrile,propionitrile, etc. are exemplified.

As the above-mentioned “organic acids”, for example, acetic acid,propionic acid, trifluoroacetic acid, etc. are exemplified.

As the above-mentioned “esters”, for example, methyl acetate, ethylacetate, amyl acetate, ethyl propionate, etc. are exemplified.

When the intended substance is obtained in the free form by theabove-mentioned reaction, it may be converted into a salt according toan ordinary method, while when obtained in the form of a salt, it canalso be converted into a free form or other salt according to anordinary method. Thus obtained compound (I) can be isolated and purifiedfrom a reaction solution by known means, for example, rolling,concentration, solvent extraction, fractionation, crystallization,recrystallization, chromatography and the like.

When the compound (I) is present as a configuration isomer,diastereomer, conformer or the like, if necessary, each can be isolatedby the above-mentioned separation and purification means. When thecompound (I) is a racemate, it can be separated into an S form and Rform by a usual optical resolution.

When a stereoisomer is present in the compound (I), this isomer aloneand mixtures thereof are also included in the present invention.

Further, the compound (I) may be a hydrate or non-hydrate.

The compound (I) may be labeled with an isotope (e.g. ³H, ¹⁴C, ³⁵S),etc.

The compound (I) of the present invention or a pro-drug thereof(hereinafter also referred to as the compound of the present invention)has an excellent p38 MAP kinase inhibitory activity, TNF-α inhibitoryactivity (TNF-α production inhibitory activity, TNF-α action inhibitoryactivity), phosphodiesterase IV (PDE IV) inhibitory activity, adenosinereceptor (e.g., adenosine A₁, A_(2a), A_(2b), A₃ receptors) antagonizingactivity and the like, further has low toxicity and few side effects.Therefore, the compound of the present invention is useful as a safemedicine such as a p38 MAP kinase inhibitor, a TNF-α productioninhibitor, a PDE IV inhibitor, an adenosine receptor (e.g., adenosineA₁, A_(2a), A_(2b) or A₃ receptor) antagonist, etc.

A pharmaceutical composition comprising the compound of the presentinvention shows an excellent p38 MAP kinase inhibitory activity andTNF-α inhibitory activity on mammals (e.g., mouse, rat, hamster, rabbit,felis, canis, bovine, ovis, monkey, human and the like) and has also anexcellent (oral)absorbing property, (metabolic) stability and the like.Therefore, this composition can be used as a pharmaceutical compositionfor preventing and/or treating p38 MAP kinase-mediated diseases andTNF-α production-mediated diseases, for example, asthma, allergicdiseases, atopic dermatitis, inflammation, inflammatory eye diseases,Addison's disease, autoimmune hemolytic anemia, systemic lupuserythematosus, psoriasis, rheumatism, central nerve disorders (e.g.,cerebrovascular disorders such as encephalorrhagy, cerebral infarctionand the like, head trauma, spinal cord injury, cerebral edema, multiplesclerosis and the like), neuro-degenerative diseases (e.g., Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis (ALS),aquired immune deficiency syndrome (AIDS) encephalopathy), meningitis,diabetes, arthritis (e.g., chronic rheumatoid arthritis, osteoarthritis,rheumatoid spondylitis, gouty arthritis, synovitis), toxaemias (e.g.,sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shocksyndrome), inflammatory bowel diseases (e.g., Crohn's disease,ulcerative colitis), inflammatory lung diseases (e.g., chronicpneumonia, pulmonary silicosis, pulmonary sarcoidosis, lungtuberculosis), or cachexias (e.g., cachexy due to infection, cancerouscachexia, cachexy due to acquired immume deficiency syndrome (AIDS)),arterial sclerosis, Creutzfeldt-Jakob disease, virus infection (e.g.,virus infection by cytomegalovirus, influenza virus, herpes virus andthe like), angina pectoris, myocardial infarction, congestive heartfailure, hepatitis, transplant, dialysis hypotension, diffuseintravascular coagulation symdrome, etc.

A pharmaceutical composition comprising the compound of the presentinvention shows an excellent adenosine receptor antagonizing activity onmammals (e.g., mouse, rat, hamster, rabbit, felis, canis, bovine, ovis,monkey, human and the like) and has also an excellent (oral) absorbingproperty, (metabolic) stability and the like. Therefore, thiscomposition can be used as a pharmaceutical composition for preventingand/or treating adenosine receptor-mediated diseases (particulaly,adenosine A₃ receptor-mediated diseases), for example, asthma, allergicdiseases, inflammation, Addison's disease, autoimmune hemolytic anemia,Crohn's disease, psoriasis, rheumatism, central nerve disorders (e.g.,cerebrovascular disorders such as encephalorrhagy, cerebral infarction,apoplectic stroke and the like, head trauma, spinal cord injury,cerebral edema, multiple sclerosis and the like), neuro-degenerativediseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophiclateral sclerosis. (ALS), diabetes and the like, preferably, centralnerve disorders, asthma, allergic disorders and the like).

Further, a pharmaceutical composition comprising the compound of thepresent invention shows an excellent PDE IV inhibitory activity, and canbe used as a pharmaceutical composition for preventing and/or treatingdiseases caused by inflammation, for example, bronchial asthma, chronicobstructive pulmonary disease (COPD), chronic rheumatoid arthritis,autoimmune diseases, diabetes mellitus, graft versus host disease,multiple sclerosis, sepsis, psoriasis, osteoporosis, depression, centralfunction degradation after cerebrovascular obturation, cerebrovasculardementia, Alzheimer's dementia, obesity, cardiac insufficiency, etc.

A pharmaceutical composition comprising the compound of the presentinvention has a low toxicity, and can be formulated, according to meansknown per se generally used in production of medicinal preparations, asit is or in admixture with a pharmacologically acceptable carrier, intofor example tablets (including sugar-coated tablet and film-coatedtablet), powders, granules, capsules (including soft capsule), liquid,injections, suppository, sustained release preparations and the like,and safely administered orally or parenterally (e.g., topical, rectal,intravenous administrations, etc.). The content of the compound of thepresent invention in the preparation of the present invention is fromabout 0.01 to about 100 wt % based on the whole preparation. This dosevaries depending on the subject to be dosed, dose route, disease,symptom and the like, and it may advantageously be administered orally,as a p38 MAP kinase-mediated disease preventive and therapeutic agent,for example to an arthritis patient (body weight: about 60 kg), in adosage of about 0.01 to about 30 mg/kg-body weight/day, preferably about0.1 to about 20 mg/kg-body weight/day, further preferably about 1 toabout 20 mg/kg-body weight/day in terms of the effective component [thecompound of the present invention], in one time or divided into severaltimes a day.

As a pharmacologically acceptable carrier which may be used inproduction of a preparation of the present invention, variousconventional organic or inorganic carrier substances are exemplified aspreparation raw materials, and for example, an excipient, brightener,binder and disintegrating agent in a solid preparation, and a solvent,solubilizer, suspending agent, isotonization agent, buffer, soothingagent and the like in a liquid preparation, etc. are exemplified.Further, if necessary, usual additives such as a preservative,antioxidant, coloring agent, sweetener, adsorbent, wetting agent and thelike can be appropriately used in suitable amount.

As the exipient, for example, lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light anhydrous silic acid, etc. areexemplified.

As the brightener, for example, magnesium stearate, calcium stearate,talc, colloidal silica, etc. are exemplified.

As the binder, for example, crystalline cellulose, sucrose, D-mannitol,dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,polyvinylpyrrolidone, starch, saccharose, gelatin, methyl cellulose,carboxymethyl cellulose sodium, etc. are exemplified.

As the disintegrating agent, for example, starch, carboxymethylcellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium,L-hydroxypropyl cellulose, etc. are exemplified.

As the solvent, for example, injection water, alcohol, propylene glycol,Macrogol, sesame oil, corn oil, olive oil, etc. are exemplified.

As the dissociation aid, for example, polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. areexemplified.

As the suspending agent, for example, surfactants such asstearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride, glycerinemonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose and the like, etc. are exemplified.

As the isotonization agent, for example, glucose, D-sorbitol, sodiumchloride, glycerine, D-mannitol, etc. are exemplified.

As the buffer, for example, buffering solutions of a phosphate, acetate,carbonate, citrate, etc. are exemplified.

As the soothing agent, for example, benzyl alcohol, etc. areexemplified.

As the preservative, for example, p-hydroxybenzoates, chlorobutanol,benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.are exemplified.

As the antioxidant, for example, a sulfite, ascorbic acid, α-tocopherol,etc. are exemplified.

Further, the compound of the present invention can be used incombination with other drugs than the compound of the present invention.

Examples of the drug which can be combined with the compound of thepresent invention (hereinafter, sometimes referred to as combinationdrug) include the following compounds.

(1) Non-steroidal Anti-inflammatory Drugs (NSAIDs)

{circle around (1)} Classical NSAIDs

Alcofenac, acechrofenac, sulindac, tolmetin, etodolac, fenoprofen,tiaprofenic acid, meclofenamic acid, meroxicam, theoxicam, lolnoxicam,nabtomen, acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine,migrenin, aspirin, mefenamic acid, flufenamic acid, dichlorophenacsodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen,ketoprofen, naproxen, pxaprozin, flurbiprofen, fenbufen, pranoprofen,frotacfenin, piroxicam, epirizole, tiaramide hydrochloride, sartoprofen,gabexate mesilate, camostat mesilate, urinastatin, colchicines,probenezide, sulfinpyrazon, benzbromarone, allopurinol, sodiumaurothiomalate, sodium hyaluronate, sodium salicylate, morphinehydrochloride, salicylic acid, atropine, scopolamine, morphine,pethidine, levorphanol, oxymorphone, or a salt thereof, and the like.

{circle around (2)} Cyclooxygenase depressants (COX-1 selectiveinhibitor, COX-2 Selective Inhibitor and the Like)

Salicylic acid derivatives (e.g., cerecoxiv, lofecoxiv, aspirin),MK-663, baldecoxiv, SC-57666, thylacoxiv, S-2474, dichlofenac,indomethacin, loxoprofen, and the like.

{circle around (3)} drugs having simultaneous COX inhibition and5-lipoxygenase inhibition

ML-300, p54 (COX inhibition & 5-lipoxygenase inhibition) and the like.

{circle around (4)} nitric oxide free type NSAIDs

(2) Disease Modifying Anti-rheumatic Drugs (DMARDs)

{circle around (1)} Gold preparation

Auranofin and the like.

{circle around (2)} Penicillamine

D-penicillamine

{circle around (3)} Sulfasalazine

{circle around (4)} Anti-malarial agent

Chloroquine and the like.

{circle around (5)} Pyrimidine synthesis inhibitor

Refulnomide and the like.

{circle around (6)} Prograph

(3) Anti-cytokine Agents

(I) Protein preparations

(i) TNF inhibitors

Ethanarcept, infliximav, D2E7, CDP-571, PASSTNF-α, soluble TNF receptor,TNF-α binding protein, anti-TNF-α antibody and the like.

(ii) Interleukin-1 inhibitors

Anaquinra (interleukin-1 receptor antagonist), soluble interleukin-1receptor and the like.

(iii) Interleukin-6 inhibitors

MRA (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody,Sant-7 (interleukin-6 receptor antagonist) and the like.

(iv) Interleukin-10 drugs

Interleukin-10 and the like.

(v) Interleukin-12 inhibitors

Anti-interleukin-12 antibody and the like.

(v) Drugs having interferon-α and -γ inhibition and TNF-α inhibitionsimultaneously AGT-1.

(II) Nonprotein preparations

(i) MAP kinase inhibitors

PD-98059 and the like.

(ii) Gene regulators

Inhibitors of a molecule related to signal transfer such as SP-100030,NF-κ, NF-κ B, IKK-1, IKK-2, AP-1 etc., and the like.

(iii) Cytokine production suppressors

T-614, SR-31747, sonatimod and the like.

(iv) TNF-α converting enzyme inhibitors

(v) Interleukin-1β converting enzyme inhibitors

HMR3480/VX-740 and the Like.

(vi) Interleukin-6 antagonists

SANT-7 and the like.

(vii) Interleukin-8 inhibitors

IL-8 antagonist, CXCR1 & CXCR2 antagonist and the like.

(viii) Chemokine antagonists

MCP-1 antagonist and the like.

(ix) Interleukin-2 receptor antagonists

Denileukin, diftitox and the like.

(x) Therapeutic vaccines

TNF-α vaccine and the like.

(xi) Gene therapeutic agents

Gene therapeutic agents intended to accentuate expression of a genehaving an anti-inflammatory action such as interleukin-4,interleukin-10, soluble interleukin-1 receptor, soluble TNF-α receptor,HSV-tk and the like.

(xii) Anti-sense compounds

ISIS-104838 and the like.

(4) Immunomodulators (Immunosuppressant)

(i) T-cell differentiation modifiers

Ethyl6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate(JP-A No. 7-118266)

(ii) Others

Methotrexate, cyclophosphamide, MX-68, atiprimode dihydrochloride,BMS-188667, CKD-461, limexolone, cyclosporin, tacrolimus, gusperimus,azathiopurine, anti-lymphocyte serum, dry sulfonated immunoglobulin,erythropoietin, colony stimulation factor, interleukin, interferon andthe like.

(5) Steroid Drugs

Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone,triamcinolone acetonide, fluocinonide, fluocinolone acetonide,prednisolone, methylprednisolone, cortisone acetate, hydrocortisone,fluorometholone, beclomethasone propionate, erythritol and the like.

(6) c-JUN N-terminal Kinase (JNK) Inhibitor

Compounds described in WO00/35906, WO00/35909, WO00/35921, WO00/64872 orWO00/75118.

(7) Others

(i) T-cell inhibitors

IR-501 (T-cell receptor peptide) and the like.

(ii) Inosine monophosphate dehydrogenase (IMPDH) inhibitors

Micophenolate mophetyl, VX-497 and the like.

(iii) Adhesive molecule inhibitors

ISIS-2302, selectin inhibitor, ELAM-1, VCAM-1, ICAM-1 and the like.

(iv) Thalidomide

(v) Monocyte therapeutic agents

Leukobax and the like.

(vi) Cathapsin inhibitors

(vii) Matrix MMPs inhibitors

BB-3644, CGS-27023A, Bay-12-9566, KB-R7785, L-758354, POL-641 and thelike.

(viii) Glucose-6-phosphate dehydrogenase inhibitors

CBF-BS2 and the like.

(ix) Hydroortate dehydrogenase (DHODH) inhibitors

(x) Phosphodiesterase IV (PDE IV) inhibitors

CG-1088 and the like.

(xi) Phospholipase A₂ inhibitors

(xii) iNOS inhibitors

NOX-200 and the like.

(xiii) Microtuble stimulants

Pacritaxel and the like.

(xiv) Microtuble inhibitors

Leumacon and the like.

(xv) MHC class II antagonists

ZD-2315 and the like.

(xvi) Prostacyclin agonists

Iloprost and the like.

(xvii) CD4 antagonists

4162W94, kelliximav and the like.

(xviii) CD23 Antagonists

(xix) LTB4 receptor antagonists

CGS-25019C and the like.

(xx) 5-lipoxygenase inhibitors

Dileuton and the like.

(xxi) Cholinesterase inhibitors

Galanthamine and the like.

(xxii) Thyrosinkinase inhibitors

YT-146 and the like.

(xxiii) Carepsin B inhibitors

(xxiv) Adenosine deaminase inhibitors

Pentostatin and the like.

(xxv) Osteogenesis stimulants

(2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamideor a salt thereof (JP-A No. 8-231659) and the like.

(xxvi) Dipeptidyl peptitase inhibitors

TMC-2A and the like.

(xxvii) TRK-530, TOK-8801

(xxviii) Collagen agonists

AI-200 and the like.

(xxix) Capsaicin cream

(xxx) Hyaluronic acid derivatives

Sinvisc 8hylan G-F 20), othovisc and the like.

(xxxi) Glucosamine sulfate

(xxxii) Amyprilose

(6) Used after Synovia Excision.

(7) Used after Therapy Using Prosorba Column.

Examples of the combination drug other than the above-mentionedcompounds include antibacterial agents, antifungal agents, antiprotozoanagents, antibiotics, antitussive and expectorants, sedatives, narcotics,antiulcer agents, antiarrhythmic agents, hypotensive diuretics,anticoagulants, tranquilizers, antipsychotics, antitumor agents,anti-hyperlipidemia agents, muscle relaxants, anticonvulsants,antidepressants, antiallergic agents, cardiac restoratives, arrhythmiatherapeutic agents, vasodilators, vasoconstrictors, hypotensivediuretics, diabetes therapeutic agents, antinarcotics, vitamin agents,vitamin derivatives, antiasthmatic agents, thamuria and acrasiatherapeutic agents, atopic dermatitis therapeutic agents, allergicgastritis therapeutic agents, vasopressor agents, endotoxin antagonistsor antibories, signal transfer inhibitors, inflammatory mediator actionsuppressants, inflammatory mediator action suppressing antibodies,anti-inflammatory mediator action suppressants, anti-inflammatorymediator action suppressing antibodies, and the like. Specific examplesthereof are listed below.

(1) Antibacterial Agents

{circle around (1)} Sulfa drugs

Sulfamethizole, sulfisoxazole, sulfamonomethoxin, sulfamethyzole,salazosulfapyridine, sulfadiazine silver and the like.

{circle around (2)} Quinoline-based antibacterial agents

Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin,ofloxacin, tosfloxacin tosilate, cyprofloxacin hydrochloride,lomefloxacin hydrochloride, sparfloxacin, fleloxacin and the like.

{circle around (3)} Anti-tuberculous agents

Isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicylic acid(calcium p-aminosalicylate), pyradinamide, ethionamide, prothionamide,rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and thelike.

{circle around (4)} Anti-acid fast bacteria drugs

Diaphenylsulfone, rifampicin and the like.

{circle around (5)} Anti-viral drugs

Idoxuridine, aciclovir, vitalavin, ganciclovir and the like.

{circle around (6)} Anti-HIV drugs

Didopsin, didanosin, sarcitavin, indinavir sulfate ethanol adduct,litonavir and the like.

{circle around (7)} Anti-spirochaeta drugs

{circle around (8)} Antibiotics

Tetracyclin hydrochloride, ampicillin, piperacillin, gentamycin,dibekacin, kanendomycin, lipidmycin, tobramycin, amikacin, fradiomycin,sisomycin, tetracycline, oxytetracycline, rolitetracycline, doxycycline,ampicillin, piperacillin, ticarcillin, cephalothin, cefapirin,cefaloridine, cefaclor, cefalexin, cefuroxadine, cefadroxil,defamandole, cefatoam, cefuroxime, cefathiam, cefathiamhexetyl,cefuroxime akycetyl, cefdinyl, cefditorenepivoxyl, ceftazidime,cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetyl, cefpirom,cefazopurane, cefepim, cefsulodin, cefmenoxime, cefmethazole, cefminox,cefaxytin, cefbuperazone, latamoquinacef, flomoquinacef, cefazolin,cefataxime, cefoperazone,ceftizoxime, moxalactam, thienamycin,sulfazesin, azthreonam, or a salt thereof, griseofulvin, lancasidines[Journal of Antibiotics, 38, 877-885 (9185)], azole-based compounds[2-[(2R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl-3-(2H,4H)-1,2,4-triazolone, fulconazole, itraconazole, etc.] and the like.

(2) Antifungal Agents

{circle around (1)} Polyethylene-based antibiotics (e.g., amphotericin,B, nystatin, trichomycin)

{circle around (2)} Griseofulvin, pyrrole nitrin and the like

{circle around (3)} Cytosine metabolism antagonists (e.g., flucytosine)

{circle around (4)} Imidazole derivatives (e.g., econazole,clotrimazole, miconazole nitrate, bihonazole, cloconazole)

{circle around (5)} Triazole derivatives (e.g., fulconazole,itraconazole)

{circle around (6)} Thiocarbamic acid derivatives (e.g., trinaphthol andthe like)

(3) Anti-protozoan Agents

Metronidazole, tinidazole, diethyl citrate carbamycin, quininehydrochloride, quinine sulfate and the like.

(4) Antitussive and Expectorants

Ephedrine hydrochloride, noscapine hydrochloride, dihydrocodeinephosphate, isoproterenol hydrochloride, ephedrine hydrochloride,methylephedrine hydrochloride, noscapine hydrochloride, allocramide,chlorophedianole, picoperidamine, chloperastine, protokylol,isoproterenol, salbutamol, terebuthaline, oxypetebanol, morphinehydrochloride, dextropetolfan hydrobromide, oxycodone hydrochloride,dimorfan phosphate, tipepidine hibenzate, pentoxyverine citrate,clofedanole hydrochloride, benzonatate, guaifenesin, bromhexinehydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcycteinehydrochloride, carbocysteine and the like.

(5) Sedatives

Chlorpromazine hydrochloride, atropine hydrochloride, phenobarbitol,barbitol, amobarbitol, pentobarbitol, thiopentanol sodium, thiamylalsodium, nitrazepam, estazolam, flurazepam, haloxazolam, triazolam,flunitrazepam, bromovalerylurea, chloral hydrate, triclofos sodium andthe like.

(6) Narcotics

(6-1) Local Anesthetics

Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucainehydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride,bupivacaine hydrohcloride, oxybuprocaine hydrochloride, ethylaminobenzoate, oxethazeine, and the like.

(6-2) General Anesthetics

{circle around (1)} Inhalation anesthetics (e.g., ether, halothane,nitrous oxide, influrane, enflurane)

{circle around (2)} Vein anesthetics (e.g., ketamine hydrochloride,droperidol, thiopental sodium, thiamylal sodium, pentobarbitol), and thelike.

(7) Anti-ulcer Agents

Methacropromide, histidin hydrochloride, lansoprazole, methocropramide,pirenzepine, cimetidine, ranitidine, famotidine, urogastrin,oxathezeine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate,gefalnate, aldioxa, teprenone, prostaglandin and the like.

(8) Arrhythmia Therapeutic Agents

{circle around (1)} Sodium channel blockers (e.g., chinidine,procaineamide, disopyramide, ajmaline, lidocaine, mexiletine, phenytoin)

{circle around (2)} Blockers (e.g., propranolol, alprenolol, bufetolol,oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, hindrol,carteolol, allotilol)

{circle around (3)} Potassium channel blockers (e.g., amiodarone)

{circle around (4)} Calcium channel blockers (e.g., verapamil,diltiazem), and the like.

(9) Hypotensive Diuretics

Hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide,trichlormetiazide, furosemide, ethacrynic acid, bumetanide, mefruside,azosemide, spironolactone, potassium canrenoate, triamterene, amiloride,acetazolamide, D-mannitol, isosorubide, aminoferine and the like.

(10) Anticoagulants

Heparin sodium, sodium citrate, activated protein C, tissue factor routeinhibitor, antithrombin III, dalteparin sodium, warfarin potassium,algatrovane, gabexate, sodium citrate, ozacrel sodium, ethylicosapentaenoate, varaprosto sodium, alprostadil, ticlopidinehydrochloride, pentoxyfylline, dipyridamole, thiokinase, urokinase,streptokinase, and the like.

(11) Tranquilizers

Diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam,cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepamm,hydroxydine, and the like.

(12) Antiphychotics

Chlorpromazine hydrochloride, prochlorperazine, trifluoroperazine,thiolidazine hydrochloride, perphenazine malate, fluphenazine enantate,prochlorperazine maleate, levomepromazine maleate, promethazinehydrochloride, haloperidol, bromperidol, spiperone, reserpine,clocapramine hydrochloride, sulpiride, zotepine and the like.

(13) Anti-tumor Agents

6-O-(N-chloroacetylcarbamoyl)fumagylol, bleomycin, methotrexate,actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin,cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil,picibanil, lenthinan, levamisole, bestatin, ajmexone, glycyrrhizin,doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycinhydrochloride, peplomycin sulfate, vincristine sulfate, illinotecanehydrochloride, cyclophosphamide, melphalan, disulfane, thiotepa,procarbazine hydrochloride, cisplatin, azathiopurine, mercaptopurine,tegafur, carmofur, cytarabine, methyltestosterone, testosteronepropioante, testosterone enantate, mepitiostane, phosphestolol,chlormazinone acetate, eupurine acetate, bucelerin acetate and the like.

(14) Anti-hyperlipidemia Agents

Clofibrate, etheyl2-chloro-3-[4-(2-methyl-2-pheylpropoxy)phenyl]propioante (Chemical andPharmaceutical Bulletin, 38, 2792 to 2796 (1990)), pravastatine,sinvastatine, probucol, bezafibrate, clinofibrate, nicomol,cholestyramine, dextran sulfate sodium and the like.

(15) Muscle Relaxants

Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride,chlorphenesin carbamate, baclofen, chlormezanone, mephenesin,clozoxazone, epirizone, thizanidine and the like.

(16) Anti-convulsants

Phenytoin, ethosuximide, acetazolamide, chloridiazepoxide, tripetadione,carbamazepine, phenobarbitol, primidone, sulthiam, sodium palpuroate,clonazepam, nitrazepam and the like.

(17) Anti-depressants

Imipramine, clomipramine, noxiptiline, phenelzine, amytriptilinehydrochloride, nortriptiline hydrochloride, amoxapine, mianserinhydrochloride, maprotiline hydrochloride, sulpiride, fluboxaminemaleate, trazodone hydrochloride and the like.

(18) Anti-allergic Agents

Diphenhydramine, chlorpheniramine, tripelenamine, methoziramine,clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglycate,tranilast, lepirinast, anlexanone, ibudilast, ketotifen, terphenazine,mequitazine, azelastin, epinastin, ozagrel hydrochloride,planlucast-hydrate, ceratrodust and the like.

(19) Cardiac Restorative

Transbiooxocamphor, telefinol, aminophylin, etilefrine, dopamine,dobutamine, denopamine, aminophylin, paecinaline, amlinone, pimobendane,ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C,G-strophanthin, and the like.

(20) Vasodilators

Oxyfedrine, diltiazem, tolazoline, hexobendine, bamethane, clonidine,methyldopa, guanabenz and the like.

(21) Vasoconstrictors

Dopamine, dobutamine, denopamine and the like.

(22) Hypotensive Diuretics

Hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine,diltiazem, nifedipine and the like.

(23) Diabetes Ttherapeutic Agents

Tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide,acalbose, epalrestat, troglytazone, glucagon, glymidine, glypzide,phenformin, puformin, metformin and the like.

(24) Antinarcotics

Levallolphan, nalorphine, naloxone, or salt thereof, and the like.

(25) Fat Soluble Vitamins

{circle around (1)} Vitamins A: vitamin A₁, vitamin A₂ and retinolpalmitate

{circle around (2)} Vitamins D: vitamins D₁, D₂, D₃, D₄ and D₅

{circle around (3)} Vitamins E: α-tocopherol, β-tocopherol,γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate

{circle around (4)} Vitamins K: vitamins K₁, K₂, K₃ and K₄

{circle around (5)} Folic Acid (vitamin M), and the Like.

(26) Vitamin Derivatives

Various derivatives of vitamins, for example, vitamin D₃ derivativessuch as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol,1-α-hydroxycholecalciferol and the like, vitamin D₂ derivatives such as5.6-trans-ergocalciferol, and the like.

(27) Anti-asthmatic Agents

Isoprenaline hydrochloride, salbutamol sulfate, procatecholhydrochloride, terbutaline sulfate, trimetoquinol hydrochloride,tulobuterol hydrochloride, orciprenaline sulfate, fenoterolhydrobromide, ephedrine hydrochloride, iprotropium bromide, oxytropiumbromide, fultropium bromide, theophyline, aminophyline, sodiumcromoglycate, tranilast, lepirinast, anlexanone, ibudilast, ketotifen,terphenazine, mequitazine, azelastin, epinastin, ozagrel hydrochloride,planlucast-hydrate, ceratrodust, dexamethasone, prednisolone,hydrocortiaone, vecropetazone propionate, and the like.

(28) Thamuria and Acrasia Therapeutic Agents

flavoxate hydrochloride and the like.

(29) Atopic Dermatitis Therapeutic Agents

Sodium cromoglycate and the like.

(30) Allergic Rhinitis Therapeutic Agents

Sodium cromoglycate, chlorpheniramine maleate, alimemazine tartarate,clemastine fumarate, homochlorcyclizine hydrochloride, terfenazine,mequitazine and the like.

(31) Vasopressors

Dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin,lanatoside C, G-strophanthin, and the like.

(32) Others

Hydroxicam, diaserine, megestrol acetate, nicerogoline, prostaglandinand the like.

Combination of compounds of the present invention with combination drugsprovide the following excellent effects:

(1) The dose can be reduced in comparison with a case in which thecompound of the present invention or a combination drug is administeredalone.

(2) A drug to be combined with the compound of the present invention canbe selected depending on symptoms (mild, serious and the like) ofpatients.

(3) The therapeutic period can be lengthened by selecting a combinationdrug having a different action mechanism than that of the compound ofthe present invention.

(4) The therapeutic effect can be sustained by selecting a combinationdrug having a different action mechanism than that of the compound ofthe present invention.

(5) By combining the compound of the present invention with acombination drug, synergic effect can be obtained.

Hereinafter, combined use of the compound (I) of the present inventionwith a combination drug is referred to as “combination agent of thepresent invention”.

In use of a combination agent of the present invention, theadministration time of the compound of the present invention and acombination drug is not restricted, and the compound of the presentinvention or a pharmaceutical composition thereof and a combination drugor a pharmaceutical composition thereof can be administered to anadministration subject simultaneously, or may be administered atdifferent times. The dosage, of a combination drug may be determinedaccording to the administration amount clinically used, and can beappropriately selected depending on an administration subject,administration route, disease, combination and the like.

The administration mode of a combination agent of the present inventionis not particularly restricted, and it is sufficient that the compoundof the present invention and a combination drug are combined inadministration. Examples of such administration mode include thefollowing methods:

(1) The compound of the present invention and a combination drug aresimultaneously produced to give a single preparation which isadministered. (2) The compound of the present invention and acombination drug are separately produced to give two kinds ofpreparations which are administered simultaneously by the sameadministration route. (3) The compound of the present invention and acombination drug are separately produced to give two kinds ofpreparations which are administered by the same administration routeonly at the different times. (4) The compound of the present inventionand a combination drug are separately produced to give two kinds ofpreparations which are administered simultaneously by the differentadministration routes. (5) The compound of the present invention and acombination drug are separately produced to give two kinds ofpreparations which are administered by the different administrationroutes only at different times (for example, the compound of the presentinvention and a combination drug are administered in this order, or inthe reverse order).

The combination agent of the present invention has low toxicity, and forexample, the compound of the present invention or (and) theabove-mentioned combination drug can be mixed, according to a methodknown per se, with a pharmacologically allowable carrier to givepharmaceutical compositions, for example, tablets (including asugar-coated tablet, film-coated tablet), powders, granules, capsules(including a soft capsule), solutions, injections, suppositories,sustained release agents and the like which can be safely administeredorally or parenterally (e.g., local, rectum, vein, and the like). Aninjection can be administered by intravenous, intramuscular,subcutaneous or intraorgan route, or directly to the lesion.

As the pharmacologically allowable carrier which may be used inproduction of a combination agent of the present invention, variousorganic or inorganic carrier substances conventionally used as apreparation raw material are exemplified, and for example, an excipient,lubricant, binder and disintegrating agent in a solid preparation, or asolvent, dissolution aid, suspending agent, isotonizing agent, buffer,soothing agent and the like in a liquid preparation, are listed.Further, if desirable, usual additives such as a preservative,antioxidant, coloring agent, sweetening agent, adsorbent, wetting agentand the like can also be appropriately used in suitable amount.

As the excipient, for example, lactose, sucrose, D-mannitol, starch,corn starch, crystalline cellulose, light anhydrous silicic acid and thelike are listed.

As the lubricant, for example, magnesium stearate, calcium stearate,talc, colloidal silica and the like are listed.

As the binder, for example, crystalline cellulose, sucrose, D-mannitol,dextrin, hydroxypropylcellulose, hydroxypropylmethylcllulose,polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose,carboxymethylcellulose sodium and the like are listed.

Examples of the disintegrating agent include starch,carboxymethylcellulose, carboxymethylcellulose calcium,carboxymethylstarch sodium, L-hydroxypropylcellulose and the like.

Examples of the solvent include injection water, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

Disclosed as examples of the dissolution aid are polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Disclosed as examples of the suspending agent are surfactants such asstearyl triethanolamine, sodium laurylsulfate, laurylaminopropionicacid, lecithine, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinyl pyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcelluose,hydroxypropylcellulose and the like.

As the isotonizing agent, for example, glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like are listed.

As the buffer, for example, buffer solutions of a phosphate, acetate,carbonate, citrate and the like, etc., are listed.

As the soothing agent, benzyl alcohol and the like are listed.

Examples of the preservative include p-oxybenzoates, chlorobutanol,benzyl alcohol, phenetyl alcohol, dehydroacetic acid, sorbic acid andthe like.

Example of the antioxidant include sulfites, ascorbic acid, α-tocopheroland the like.

The compounding ratio of the compound of the present invention to acombination drug in a combination agent in the present invention can beappropriately selected depending on an administration subject,administration route, diseases and the like.

For example, the content of the compound of the present invention in acombination agent of the present invention differs depending on the formof a preparation, and usually from about 0.01 to 100% by weight,preferably from about 0.1 to 50% by weight, further preferably fromabout 0.5 to 20% by weight, based on the preparation.

The content of a combination drug in a combination agent of the presentinvention differs depending on the form of a preparation, and usuallyfrom about 0.01 to 100% by weight, preferably from about 0.1 to 50% byweight, further preferably from about 0.5 to 20% by weight, based on thepreparation.

The content of additives such as a carrier and the like in a combinationagent of the present invention differs depending on the form of apreparation, and usually from about 1 to 99.99% by weight, preferablyfrom about 10 to 90% by weight, based on the preparation.

In the case when the compound of the present invention and a combinationdrug are separately prepared respectively, the same contents may beadopted.

These preparations can be produced by a method known per se usually usedin a preparation process.

For example, the compound of the present invention and a combinationdrug can be made into an aqueous injection together with a dispersingagent (e.g., Tween 80 (manufactured by Atlas Powder, US), HCO 60(manufactured by Nikko Chemicals), polyethylene glycol,carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose,dextrin and the like), a stabilizer (e.g., ascorbic acid, sodiumpyrosulfite, and the like), a surfactant (e.g., Polysorbate 80, macrogoland the like), a solubilizer (e.g., glycerin, ethanol and the like), abuffer (e.g., phosphoric acid and alkali metal salt thereof, citric acidand alkali metal salt thereof, and the like), an isotonizing agent(e.g., sodium chloride, potassium chloride, mannitol, sorbitol, glucoseand the like), a pH regulator (e.g., hydrochloric acid, sodium hydroxideand the like), a preservative (e.g., ethyl p-oxybenzoate, benzoic acid,methylparaben, propylparaben, benzyl alcohol and the like), a dissolvingagent (e.g., conc. glycerin, meglumine and the like), a dissolution aid(e.g., propylene glycol, sucrose and the like), a soothing agent (e.g.,glucose, benzyl alcohol and the like), and the like, or can bedissolved, suspended or emulsified in a vegetable oil such as olive oil,sesame oil, cotton seed oil, corn oil and the like or a dissolution aidsuch as propylene glycol and molded into an oily injection.

In the case of a preparation for oral administration, an excipient(e.g., lactose, sucrose, starch and the like), a disintegrating agent(e.g., starch, calcium carbonate and the like), a binder (e.g., starch,gum Arabic, carboxymethylcellulose, polyvinylpyrrolidone,hydroxpropylcellulose and the like), a lubricant (e.g., talc, magnesiumstearate, polyethylene glycol 6000 and the like) and the like, forexample, can be added to the compound of the present invention or acombination drug, according to a method known per se, and the mixturecan be compression-molded, then if desirable, the molder product can becoated by a method known per se for the purpose of masking of taste,enteric property or durability, to obtain a preparation for oraladministration. As this coating agent, for example,hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose,hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,hydroxymethylcellulose stearate succinate, Eudoragit (methacrylicacid•acrylic acid copolymer, manufactured by Rohm, D E), pigment (e.g.,iron oxide red, titanium dioxide, et.) and the like can be used. Thepreparation for oral administration may be any of a quick releasepreparation and a sustained release preparation.

For example, in the case of a suppository, the compound of the presentinvention and a combination drug can be made into an oily or aqueoussolid, semisolid or liquid suppository according to a method known perse.

As the oily substrate used in the above-mentioned composition, forexample, glycerides of higher fatty acids [e.g., cacao butter, Witebsols(manufactured by Dynamite Novel, D E), etc.], intermediate grade fattyacids [e.g., Myglyols (manufactured by Dynamite Novel, D E), etc.], orvegetable oils (e.g., sesame oil, soy bean oil, cotton seed oil and thelike), and the like are listed. Further, as the aqueous substrate, forexample, polyethylene glycols, propylene glycol are listed, and as theaqueous gel substrate, for example, natural gums, cellulose derivatives,vinyl polymers, acrylic acid polymers and the like are listed.

As the above-mentioned sustained release agent, sustained releasemicrocapsules and the like are listed.

For obtaining a sustained release microcapsule, a method known per secan be adopted, and for example, it is preferably molded into asustained release preparation shown in the following [2] beforeadministration.

The compound of the present invention is preferably molded into an oraladministration preparation such as a solid preparation (e.g., powder,granule, tablet, capsule) and the like, or molded into a rectumadministration preparation such as a suppository. Particularly, an oraladministration preparation is preferable.

A combination drug can be made into the above-mentioned drug formdepending on the kind of the drug.

[1] An injection of the compound of the present invention or acombination drug, and preparation thereof, [2] a sustained releasepreparation or quick release preparation of the compound of the presentinvention or a combination drug, and preparation thereof, [3] asublingual, buccal or intraoral quick disintegrating agent of thecompound of the present invention or a combination drug, and preparationthereof, will be specifically described below.

[1] Injection and Preparation Thereof

An injection prepared by dissolving the compound of the presentinvention or a combination drug into water is preferable. This injectionmay be allowed to contain a benzoate and/or salicylate.

The injection is obtained by dissolving the compound of the presentinvention or a combination drug, and if desirable, a benzoate and/orsalicylate, into water.

As the above-mentioned salts of benzoic acid and salicylic acid, forexample, salts of alkali metals such as sodium, potassium and the like,salts of alkaline earth metals such as calcium, magnesium and the like,ammonium salts, meglumine salts, organic acid salts such as tromethamoland the like, etc. are listed.

The concentration of the compound of the present invention or acombination drug in an injection is from 0.5 to 50 w/v %, preferablyfrom about 3 to 20 w/v %. The concentration of a benzoate salt or/andsalicylate salt is from 0.5 to 50 w/v %, preferably from 3 to 20 w/v %.

Into a preparation of the present invention, additives usually used inan injection, for example, a stabilizer (ascorbic acid, sodiumpyrosulfite, and the like), a surfactant (Polysorbate 80, macrogol andthe like), a solubilizer (glycerin, ethanol and the like), a buffer(phosphoric acid and alkali metal salt thereof, citric acid and alkalimetal salt thereof, and the like), an isotonizing agent (sodiumchloride, potassium chloride, and the like), a dispersing agent(hydroxypropylmethylcellulose, dextrin), a pH regulator (hydrochloricacid, sodium hydroxide and the like), a preservative (ethylp-oxybenzoate, benzoic acid and the like), a dissolving agent (conc.glycerin, meglumine and the like), a dissolution aid (propylene glycol,sucrose and the like), a soothing agent (glucose, benzyl alcohol and thelike), and the like, can be appropriately compounded. These additivesare generally compounded in a proportion usually used in an injection.

It is advantageous that pH of an injection is controlled from 2 to 12,preferably from 2.5 to 8.0 by addition of a pH regulator.

An injection is obtained by dissolving the compound of the presentinvention or a combination drug and if desirable, a benzoate and/or asalicylate, and if necessary, the above-mentioned additives into water.These may be dissolved in any order, and can be appropriately dissolvedin the same manner as in a conventional method of producing aninjection.

An aqueous solution for injection may be advantageously be heated,alternatively, for example, filter sterilization, high pressure heatsterilization and the like can be conducted in the same manner as for ausual injection, to provide an injection.

It may be advantageous that an aqueous solution for injection issubjected to high pressure heat sterilization at 100 to 121° C. for 5 to30 minutes.

Further, a preparation endowed with an antibacterial property of asolution may also be produced so that it can be used as a preparationwhich is divided and administered multiple-times.

[2] Sustained Release Preparation or Quick Release Preparation, andPreparation Thereof

A sustained release preparation is preferable which is obtained, ifdesirable, by coating a nucleus containing the compound of the presentinvention or a combination drug with a film agent such as awater-insoluble substance, swellable polymer and the like. For example,a sustained release preparation for oral administration of onceadministration per day type is preferable.

As the water-insoluble substance used in a film agent, there are listed,for example, cellulose ethers such as ethylcellulose, butylcellulose andthe like, cellulose esters such as cellulose stearate, cellulosepropionate and the like, polyvinyl esters such as polyvinyl acetate,polyvinyl butyrate and the like, acrylic acid/methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethylmethacrylate/cinnamoethyl methacryalte/aminoalkyl methacrylatecopolymers, polyacrylic acid, polymethacrylic acid, methacrylic acidalkylamide copolymers poly(methyl methacrylate), polymethacrylate,polymethacrylamide, aminoalkyl methacryalte copolymers, poly(methacrylicanhydride), glycidyl methacrylate copolymer, particularly, acrylicacid-based polymers such as Eudoragits (Rhom Farma) such as EudoragitRS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acryalte•methylmethacryalte•trimethyl chloride methacryalte•ammoniumethyl copolymer),Eudoragit NE-30D (methyl methacryalte•ethyl acrylate copolymer), and thelike, hardened oils such as hardened castor oil (e.g., Lovery wax(Freunt) and the like), waxes such as carnauba wax, fatty acid glycerinester, paraffin and the like, polyglycerin fatty esters, and the like.

As the swellable polymer, polymers having an acidic dissociating groupand showing pH dependent swell are preferable, and polymers manifestingsmall swelling in acidic regions such as in stomach and large swellingin neutral regions such as in small intestine and large intestine arepreferable.

As such a polymer having an acidic dissociating group and showing pHdependent swell, cross-linkable polyacrylic acid copolymers such as, forexample, Carbomer 934P, 940, 941, 974P, 980, 1342 and the like,polycarbophil (calcium polycarbophil (last two are manufactured by B FGoodrich), Hibiswako 103, 104, 105, 304 (all are manufactured by WakoPurechemical Co., Ltd.), and the like, are listed.

The film agent used in a sustained release preparation may furthercontain a hydrophilic substance.

As the hydrophilic substance, for example, polysaccharides which maycontain a sulfate group such as pullulan, dextrin, alkali metal alginateand the like, polysaccharides having a hydroxyalkyl group orcarboxyalkyl group such as hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose sodium and thelike, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol,polyethylene glycol and the like are listed.

The content of a water-insoluble substance in the film agent of asustained release preparation is from about 30 to 90% (w/w), preferablyfrom about 35 to 80% (w/w), further preferably from about 40 to 75%(w/w), the content of a swellable polymer is from about 3 to 30% (w/w),preferably from about 3 to 15% (w/w). The film agent may further containa hydrophilic substance, and in which case, the content of a hydrophilicsubstance in the film agent is about 50% (w/w) or less, preferably about5 to 40% (w/w), further preferably from about 5 to 35% (w/w). This %(w/w) indicates % by weight based on a film agent composition which isobtained by removing a solvent (e.g., water, lower alcohols such asmethanol, ethanol and the like) from a film agent solution.

The sustained release preparation is produced by preparing a nucleuscontaining a drug as exemplified below, then, coating the resultingnucleus with a film agent solution prepared by heat-solvating awater-insoluble substance, swellable polymer and the like or bydissolving or dispersing it in a solvent.

I. Preparation of Nucleus Containing Drug

The form of nucleus containing a drug to be coated with a film agent(hereinafter, sometimes simply referred to as nucleus) is notparticularly restricted, and preferably, the nucleus is formed intoparticles such as a granule or fine particle.

When the nucleus is composed of granules or fine particles, the averageparticle size thereof is preferably from about 150 to 2000 μm, furtherpreferably, from about 500 to 1400 μm.

Preparation of the nucleus can be effected by a usual production method.For example, a suitable excipient, binding agent, integrating agent,lubricant, stabilizer and the like are mixed into a drug, and themixture is subjected to a wet extrusion granulating method, fluidizedbed granulating method or the like, to prepare a nucleus.

The content of drugs in a nucleus is from about 0.5 to 95% (w/w),preferably from about 5.0 to 80% (w/w), further preferably from about 30to 70% (w/w).

As the excipient contained in the nucleus, for example, saccharides suchas sucrose, lactose, mannitol, glucose and the like, starch, crystallinecellulose, calcium phosphate, corn starch and the like are used. Amongthem, crystalline cellulose, corn starch are preferable.

As the binder, for example, polyvinyl alcohol, hydroxypropyl cellulose,polyethylene glycol, polyvinyl pyrrolidone, Pluronic F68, gum Arabic,gelatin, starch and the like are used. As the disintegrating agent, forexample, carboxymethylcellulose calcium (ECG505), crosscarmelose sodium(Ac-Di-Sol), crosslinked polyvinylpyrrolidone (Crosspovidone), lowersubstitution hydroxypropylcellulose (L-HPC) and the like are used. Amongthem, hydroxypropylcellulose, polyvinylpyrrolidone, lower substitutionhydroxypropylcellulose are preferable. As the lubricant and coagulationinhibitor, for example, talc, magnesium stearate and inorganic saltsthereof are used, and as the lubricant, polyethylene glycol and the likeare used. As the stabilizer, acids such as tartaric acid, citric acid,succinic acid, fumaric acid, maleic acid and the like, are used.

A nucleus can also be prepared by, in addition to the above-mentioned,for example, a rolling granulation method in which a drug or a mixtureof a drug with an excipient, lubricant and the like is added portionwiseonto an inert carrier particle which is the core of the nucleus whilespraying a binder dissolved in a suitable solvent such as water, loweralcohol (e.g., methanol, ethanol and the like) and the like, a pancoating method, a fluidized bed coating method or a melt granulatingmethod. As the inert carrier particle, for example, those made ofsucrose, lactose, starch, crystalline cellulose, waxes can be used, andthe average particle size thereof is preferably from about 100 μm to1500 μm.

For separating a drug and a film agent contained in a nucleus, thesurface of the nucleus may be coated with a protective agent. As theprotective agent, for example, the above-mentioned hydrophilicsubstances, water-insoluble substances and the like are used. As theprotective agent, preferably polyethylene glycol, and polysaccharideshaving a hydroxyalkyl group or carboxyalkyl group are used, morepreferably, hydroxypropylmethylcellulose and hydroxypropyplcellulose areused. The protective agent may contain, as a stabilizer, acids such astartaric acid, citric acid, succinic acid, fumaric acid, maleic acid andthe like, and lubricants such as talc and the like. When the protectiveagent is used, the coating amount is from about 1 to 15% (w/w),preferably from about 1 to 10% (w/w), further preferably from about 2 to8% (w/w), based on the nucleus.

The protective agent can be coated by a usual coating method, andspecifically, the protective agent can be coated, for example, by afluidized bed coating method, pan coating method and the like.

II. Coating of Nucleus with Film Agent

A nucleus obtained in the above-mentioned step I is coated with a filmagent solution obtained by heat-solvating the above-mentionedwater-insoluble substance and pH-dependent swellable polymer, and ahydrophilic substance, or by dissolving or dispersing them in a solvent,to give a sustained release preparation.

As the method for coating a nucleus with a film agent solution, forexample, a spray coating method and the like are listed.

The composition ratio of a water-insoluble substance, swellable polymerand hydrophilic substance in a film agent solution is appropriatelyselected so that the contents of these components in a coated film arethe above-mentioned contents, respectively.

The coating amount of a film agent is from about 1 to 90% (w/w),preferably from about 5 to 50% (w/w), further preferably from about 5 to35% (w/w), based on a nucleus (not including coating amount ofprotective agent).

As the solvent in a film agent solution, water or an organic solvent canbe used alone or in admixture thereof. In the case of use in admixture,the mixing ratio of water to an organic solvent (water/organic solvent:by weight) can be varied in the range from 1 to 100%, and preferablyfrom 1 to about 30%. The organic solvent is not particularly restrictedproviding it dissolves a water-insoluble substance, and for example,lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol,n-butyl alcohol and the like, lower alkanone such as acetone and thelike, acetonitrile, chloroform, methylene chloride and the like areused. Among them, lower alcohols are preferable, and ethyl alcohol andisopropyl alcohol are particularly preferable. Water, and a mixture ofwater with an organic solvent are preferably used as a solvent for afilm agent. In this case, if necessary, an acid such as tartaric acid,citric acid, succinic acid, fumaric acid, maleic acid and the like mayalso be added into a film agent solution for stabilizing the film agentsolution.

An operation of coating by spray coating can be effected by a usualcoating method, and specifically, it can be effected by spray-coating afilm agent solution onto a nucleus by a fluidized bed coating method,pan coating method and the like. In this case, if necessary, talc,titanium oxide, magnesium stearate, calcium stearate, light anhydroussilicic acid and the like may also be added as a lubricant, and glycerinfatty ester, hardened castor oil, triethyl citrate, cetyl alcohol,stearyl alcohol and the like may also be added as a plasticizer.

After coating with a film agent, if necessary, an antistatic agent suchas talc and the like may be mixed.

The quick release preparation may be liquid (solution, suspension,emulsion and the like) or solid (particle, pill, tablet and the like).Oral agents and parenteral agents such as an injection and the like areused, and oral agents are preferable.

The quick release preparation, usually, may contain, in addition to anactive component drug, also carriers, additives and excipientsconventionally used in the production field (hereinafter, sometimesabbreviated as excipient). The preparation excipient used is notparticularly restricted providing it is an excipient ordinarily used asa preparation excipient. For example, as the exipient for an oral solidpreparation, lactose, starch, corn starch, crystalline cellulose (AcevilPH101, manufactured by Asahi Chemical Industry Co., Ltd., and the like),powder sugar, granulated sugar, mannitol, light anhydrous silicic acid,magnesium carbonate, calcium carbonate, L-cysteine and the like arelisted, and preferably, corn starch and mannitol and the like arelisted. These excipients can be used alone or in combination of two ormore. The content of the excipient is, for example, from about 4.5 to99.4 w/w %, preferably from about 20 to 98.5 w/w %, further preferablyfrom about 30 to 97 w/w %, based on the total amount of the quickrelease preparation.

The content of a drug in the quick release preparation can beappropriately selected in the range from about 0.5 to 95%, preferablyfrom about 1 to 60% based on the total amount of the quick releasepreparation.

When the quick release preparation is an oral solid preparation, itusually contains, in addition to the above-mentioned components, also adisintegrating agent. As this disintegrating agent, there are used, forexample, carboxymethylcellulose calcium (ECG-505, manufactured by GotokuYakuhin), crosscarmelose sodium (for example, Actisol, manufactured byAsahi Chemical Industry Co., Ltd.), crosspovidone (for example, ColiconeCL, manufactured by BASF), lower substitution hydroxypropylcellulose(manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethylstarch(manufactured by Matsutani Kagaku K. K.), carboxymethylstarch sodium(Exprotab, manufactured by Kimura Sangyo), partially α-nized starch(PCS, manufactured by Asahi Chemical Industry Co., Ltd.), and the likeare used, and for example, those which disintegrate a granule byadsorbing water in contact with water, causing swelling, or making achannel between an effective ingredient constituting the nucleus and anexcipient, can be used. These disintegrating agents can be used alone orin combination of two or more. The amount of the disintegrating agentused is appropriately selected depending on the kind and compoundingamount of a drug used, design of releasing property, and the like, andfor example, from about 0.05 to 30 w/w %, preferably from about 0.5 to15 w/w %, based on the total amount of the quick releasing agent.

When the quick release preparation is an oral solid preparation, it mayfurther contain, in addition to the above-mentioned composition, ifdesired, additives conventional in solid preparations. As such anadditive, there are used, for example, a binder (e.g., sucrose, gelatin,gum Arabic powder, methylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxylmethylcellulose,polybinylpyrrolidone, pluran, dextrin and the like), a lubricant (e.g.,polyethylene glycol, magnesium stearate, talc, light anhydrous silicicacid (for example, aerosil (Nippon Aerosil)), a surfactant (e.g.,anionic surfactants such as sodium alkylsulfate and the like, nonionicsurfactants such as polyoxyethylene fatty acid ester and polyoxyethylenesorbitan fatty acid ester, polyoxyethylene castor oil derivatives andthe like), a coloring agent (e.g., tar coloring matter, caramel, ironoxide red, titanium oxide, riboflavins), if necessary, an appetizingagent (e.g., sweetening agent, aroma and the like), an adsorbent,preservative, wetting agent, antistatic agent, and the like. Further, asthe stabilizer, an organic acid such as tartaric acid, citric acid,succinic acid, fumaric acid and the like may also be added.

As the above-mentioned binder, hydroxypropylcellulose, polyethyleneglycol and polyvinylpyrrolidone and the like are preferably used.

The quick releasing reparation can be prepared by, based on a usualtechnology of producing preparations, mixing the above-mentionedcomponents, and if necessary, further kneading the mixture, and moldingit. The above-mentioned mixing is conducted by generally used methods,for example, mixing, kneading and the like. Specifically, when a quickrelease preparation is formed, for example, into a particle, it can beprepared., according to the same means as in the above-mentioned methodfor preparing a nucleus of a sustained release preparation, by mixingthe components using a vertical granulator, universal kneader(manufactured by Hata Tekkosho), fluidized bed granulator FD-5S(manufactured by Pulek), and the like, then, subjecting the mixture to awet extrusion granulation method, fluidized bed granulation method andthe like.

Thus obtained quick releasing preparation and sustained releasingpreparation may be themselves made into products or made into productsappropriately together with preparation excipients and the like,separately, by an ordinary method, then, may be administeredsimultaneously or may be administered in combination at anyadministration interval, or they may be themselves made into one oralpreparation (e.g., granule, fine particle, tablet, capsule and the like)or made into one oral preparation together with preparation excipientsand the like. It may also be permissible that they are made intogranules or fine particles, and filled in the same capsule to be used asa preparation for oral administration.

[3] Sublinguial, Buccal or Intraoral Quick Disintegrating Agent andPreparation thereof

Sublinguial, buccal or intraoral quick disintegrating agents may be asolid preparation such as tablet and the like, or may be an oral mucosamembrane patch (film).

As the sublinguial, buccal or intraoral quick disintegrating agent, apreparation containing the compound of the present invention or acombination drug and an excipient is preferable. It may contain alsoauxiliary agents such as a lubricant, isotonizing agent, hydrophiliccarrier, water-dispersible polymer, stabilizer and the like. Further,for easy absorption and increase in in vivo use efficiency,β-cyclodextrin or β-cyclodextrin derivatives (e.g.,hydroxypropyl-β-cyclodextrin and the like) and the like may also becontained.

As the above-mentioned excipient, lactose, sucrose, D-mannitol, starch,crystalline cellulose, light anhydrous silicic acid and the like arelisted. As the lubricant, magnesium stearate, calcium stearate, talc,colloidal silica and the like are listed, and particularly, magnesiumstearate and colloidal silica are preferable. As the isotonizing agent,sodium chloride, glucose, fructose, mannitol, sorbitol, lactose,saccharose, glycerin, urea and the like are listed, and particularly,mannitol is preferable. As the hydrophilic carrier, swellablehydrophilic carriers such as crystalline cellulose, ethylcellulose,crosslinkable polyvinylpyrrolidone, light anhydrous silicic acid,silicic acid, dicalcium phosphate, calcium carbonate and the like arelisted, and particularly, crystalline cellulose (e.g., fine crystallinecellulose and the like) is preferable. As the water-dispersible polymer,gums (e.g., gum tragacanth, acacia gum, cyamoposis gum), alginates(e.g., sodium alginate), cellulose derivatives (e.g., methylcellulose,carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose), gelatin, water-soluble starch,polyacrylic acids (e.g., Carbomer), polymethacylic acid, polyvinylalcohol, polyethylene glycol, polyvinylpyrrolicone, polycarbofil,ascorbate palmitates and the like are listed, andhydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin,carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol andthe like are preferable. Particularly, hydroxypropylmethylcellulose ispreferable. As the stabilizer, cysteine, thiosorbitol, tartaric acid,citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfiteand the like are listed, and particularly, citric acid and ascorbic acidare preferable.

The sublinguial, buccal or intraoral quick disintegrating agent can beproduced by mixing the compound of the present invention or acombination drug and an excipient by a method known per se. Further, isdesirable, auxiliary agents such as a lubricant, isotonizing agent,hydrophilic carrier, water-dispersible polymer, stabilizer, coloringagent, sweetening agent, preservative and the like may be mixed. Thesublingual, buccal or intraoral quick disintegrating agent is obtainedby mixing the above-mentioned components simultaneously or at a timeinterval, then subjecting the mixture to tablet-making molding underpressure. For obtaining suitable hardness, it may also be permissiblethat the materials are moistened by using a solvent such as water,alcohol and the like if desired before and after the tablet makingprocess, and after the molding, the materials are dried, to obtain aproduct.

In the case of molding into a mucosa membrane patch (film), the compoundof the present invention or a combination drug and the above-mentionedwater-dispersible polymer (preferably, hydroxypropylcellulose,hydroxypropylmethylcellulose), excipient and the like are dissolved in asolvent such as water and the like, and the resulted solution is cast,to give a film. Further, additives such as a plasticizer, stabilizer,antioxidant, preservative, coloring agent, buffer, sweetening agent andthe like may also be added. For imparting suitable elasticity to thefilm, glycols such as polyethylene glycol, propylene glycol and the likemay be contained, or for enhancing adhesion of the film to an intraoralmucosa membrane lining, a bio-adhesive polymer (e.g., polycarbofil,carbopol) may also be contained. In the casting, a solution is poured onthe non-adhesive surface, spread to uniform thickness (preferably, about10 to 1000 micron) by an application tool such as a doctor blade and thelike, then, the solution is dried to form a film. It may be advantageousthat thus formed film is dried at room temperature or under heat, andcut into given area.

As the preferable intraoral quick disintegrating agent, there are listedsolid quick scattering dose agents composed of a network body comprisingthe compound of the present invention or a combination drug, and awater-soluble or water-diffusible carrier which is inert to the compoundof the present invention or combination drug, are listed. This networkbody is obtained by sublimating a solvent from the solid compositionconstituted from a solution prepared by dissolving the compound of thepresent invention or a combination drug in a suitable solvent.

It is preferable that the composition of an intraoral quickdisintegrating agent contains a matrix forming agent and a secondarycomponent, in addition to the compound of the present invention or acombination drug.

Examples of the matrix forming agent include animal proteins orvegetable proteins such as gelatins, dextrins and, soybean, wheat andpsyllium seed protein and the like; rubber substances such as gumArabic, guar gum, agar, xathane gum and the like; polysaccharides;alginic acids; carboxymethylcelluloses; carageenans; dextrans; pectines;synthetic polymers such as polyvinylpyrrolidone and the like; substancesderived from a gelatin-gum Arabic complex, and the like. Further,saccharides such as mannitol, dextrose, lactose, galactose, trehaloseand the like; cyclic saccharides such as cyclodextrin and the like;inorganic salts such as sodium phosphate, sodium chloride and aluminumsilicate and the like; amino acids having 2 to 12 carbon atoms such asglycine, L-alanine, L-asparatic acid, L-glutamic acid, L-hydroxyproline,L-isoleucine, L-leucine, L-phenylalanine and the like, are losted.

One or more of the matrix forming agents can be introduced in a solutionor suspension before solidification. Such a matrix forming agent may bepresent in addition to a surfactant, or may be present while asurfactant is being excluded. The matrix forming agent aids to maintainthe compound of the present invention or a combination drug in thesolution or suspension in diffused condition, in addition to formationof the matrix.

The composition may contain secondary components such as a preservative,antioxidant, surfactant, thickening agent, coloring agent, pHcontrolling agent, flavoring agent, sweetening agent, food taste maskingagent and the like. As the suitable coloring agent, there are listedred, black and yellow iron oxides, and FD & C dyes such as FD & C Blue2, FD &. C Red 40 and the like manufactured by Elis and Eberald.Examples of the suitable flavoring agent include mint, raspberrylicorice, orange, lemon, grape fruit, caramel, vanilla, cherry, grapeflavor and combinations thereof. Examples of the suitable pH controllingagent include citric acid, tartaric acid, phosphoric acid, hydrochloricacid and maleic acid. Examples of the suitable sweetening agent includeaspartame, acesulfame K and thaumatin and the like. Examples of thesuitable food taste masking agent include sodium bicarbonate, ionexchange resin, cyclodextrin-containing compounds, adsorbent substancesand microcapsulated compounds.

The preparation contains the compound of the present invention or acombination drug in an amount usually from about 0.1 to 50% by weight,preferably from about 0.1 to 30% by weight, and preferable arepreparations (such as the above-mentioned sublingual agent, buccal andthe like) which can dissolve 90% or more the compound of the presentinvention or a combination drug (into water) within the time range ofabout 1 to 60 minutes, preferably of about 1 to 16 minutes, morepreferably of about 2 to 5 minutes, and intraoral quick disintegratingpreparations which are disintegrated within the range of 1 to 60seconds, preferably of 1 to 30 seconds, further preferably of 1 to 10seconds after being placed in an oral cavity.

The content of the above-mentioned exipient in the whole preparation isfrom about 10 to 99% by weight, preferably from about 30 to 90% byweight. The content of β-cyclodextrin or β-cyclodextrin derivative inthe whole preparation is from 0 to about 30% by weight. The content ofthe lubricant in the whole preparation is from about 0.01 to 10% byweight, preferably from about 1 to 5% by weight. The content of theisotonizing agent in the whole preparation is from about 0.1 to 90% byweight, preferably, from about 10 to 70% by weight. The content of thehydrophilic carrier agent in the whole preparation is from about 0.1 to50% by weight, preferably, from about 10 to 30% by weight. The contentof the water-dispersible polymer in the whole preparation is from about0.1 to 30% by weight, preferably, from about 10 to 25% by weight. Thecontent of the stabilizer in the whole preparation is from about 0.1 to10% by weight, preferably, from about 1 to 5% by weight. Theabove-mentioned preparation may further contain additives such as acoloring agent, sweetening agent, preservative and the like, ifnecessary.

The dosage of a combination agent of the present invention differsdepending on the kind of compound (I), age, body weight, condition, drugform, administration method, administration period and the like, and forexample, for one sepsis patient (adult, body weight: about 60 kg), thecombination agent is administered intravenously, at a dose of about 0.01to 1000 mg/kg/day, preferably about 0.01 to 100 mg/kg/day, morepreferably about 0.1 to 100 mg/kg/day, particularly about 0.1 to 50mg/kg/day, especially about 1.5 to 30 mg/kg/day, in terms of thecompound of the present invention or a combination drug, respectively,once or apportioned to several times in a day. Of course, since the doseas described above varies depending on various conditions, amountssmaller than the above-mentioned dosage may sometimes be sufficient,further, amounts over that range sometimes have to be administered.

The amount of a combination drug can be set at any value unless sideeffects are problematic. The daily dosage in terms of a combination drugdiffers depending on the severity, age, sex, body weight, sensitivitydifference of the subject, administration period, interval, and nature,pharmacy, kind of the pharmaceutical preparation, kind of effectiveingredient, and the like, and is not particularly restricted, and theamount of a drug is, in the case of oral administration for example,usually from about 0.001 to 2000 mg, preferably from about 0.01 to 500mg, further preferably from about 0.1 to 100 mg, per 1 kg of a mammaland this is usually administered once or divided into 4-times a day.

In the administration of a medicine of the present invention, thecompound of the present invention may be administered afteradministration of a combination drug or a combination drug may beadministered after administration of the compound of the presentinvention, though they may be administered simultaneously. Whenadministered at a time interval, the interval differs depending on theeffective ingredient, drug form and administration method, and forexample, when a combination drug is administered first, a method inwhich the compound of the present invention is administered within atime range of from 1 minute to 3 days, preferably from 10 minutes to 1day, more preferably from 15 minutes to 1 hour after administration ofthe combination drug is exemplified. When the compound of the presentinvention is administered first, a method in which a combination drug isadministered within a time range of from 1 minute to 1 day, preferablyfrom 10 minutes to 6 hours, more preferably from 15 minutes to 1 hourafter administration of the compound of the present invention isexemplified.

In a preferable administration method, for example, a combination drugwhich has been formed into an oral administration preparation isadministered orally at a daily dose of about 0.001 to 200 mg/kg, and 15minutes after, the compound of the present invention which has beenformed into an oral administration preparation is administered orally ata daily dose of about 0.005 to 100 mg/kg.

BEST MODE OF CARRYING OUT THE INVENTION

The following reference examples, examples, preparation examples andexperiments will illustrate the present invention further in detailbelow, but these are only examples and do not limit the scope of thepresent invention, and further, may be varied within a range which isnot outside the range of the present invention.

In the following reference examples and example, room temperature” meansusually temperatures from about 10° C. to about 35° C. “%” is by weightunless otherwise stated. Yield is represented by mol/mol %.

Abbreviations used in this text have the following meanings.

S; singlet d: doublet t: triplet q: quartet dd: double doublet ddd:double double doublet dt: double triplet br: broad J: coupling constantHz: Hertz CDCl₃: deuterium chloroform DMSO-d₆: dimethylsulfoxide-d₆¹H-NMR: proton nuclear magnetic resonance spectrum Me: methyl

Sequence numbers in the sequence table of the present specification meanthe following sequences.

[SEQ ID No. 1]

It indicates a nucleotide sequence of a primer p38-U used in Example 1.

[SEQ ID No. 2]

It indicates a nucleotide sequence of a primer PAG-L used in Example 1.

[SEQ ID No. 3]

It indicates a nucleotide sequence of a primer MKK-U used in Example 1.

[SEQ ID No. 4]

It indicates a nucleotide sequence of a primer MKK-L used in Example 1.

[SEQ ID No. 5]

It indicates a nucleotide sequence of a primer SER-U used in Example 1.

[SEQ ID No. 6]

It indicates a nucleotide sequence of a primer SER-L used in Example 1.

WORKING EXAMPLE Reference Example 1

1-bromo-3-ethylbenzene

To a solution of 3-ethylaniline (10.0 g, 82.5 mmol) in 50% sulfanic acid(43.6 g) was added dropwise an aqueous solution (16.5 mL) of sodiumnitrite (6.83 g, 99.0 mmol) over 30 minutes at 0° C. The resultingreaction mixture was stirred for 45 minutes at 0° C. This diazonium saltsolution was added dropwise to a solution of copper (I) bromide (12.4 g,86.6 mmol) in a 48% hydrobromic acid (82.5 mL) while heating gentlyunder reflux. After the addition, the reaction mixture was heated toreflux for 30 minutes. The reaction mixture was cooled to roomtemperature, and extracted with ether. The extracts were sequentiallywashed with a 1N-aqueous sodium hydroxide solution and brine, andfiltrated, dried, and concentrated. The residue was purified by silicagel column chromatography (hexane-ethyl acetate=20:1) to obtain a titlecompound (6.13 g, yield 40%).

Oil

¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=7.5 Hz), 2.63 (2H, q, J=7.5 Hz),7.11-7.20 (2H, m), 7.28-7.38 (2H, m).

Reference Example 2

The following reference example compound 2 was synthesized according toReference Example 1, using 3-(1-methylethyl)aniline instead of3-ethylaniline.

Reference Example Compound 2

1-bromo-3-(1-methylethyl)benzene

Oil

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=7.0 Hz), 2.77-2.99 (1H, m), 7.03-7.16(2H, m), 7.27-7.34 (1H, m), 7.37 (1H, s).

Reference Example 3

3-ethylbenzoic acid

Under an argon atmosphere, a solution of 1-bromo-3-ethylbenzene (5.1 g,28 mmol) in tetrahydrofuran (45 mL) was added dropwise to a mixture ofmagnesium turnings (0.74 g, 31 mmol) in tetrahydrofuran (5.0 mL), andthe mixture was stirred for 30 minutes under the same condition. Thereaction mixture was added to crashed dry ice, and the mixture wasstirred for 1 hour. To the reaction mixture was added 1N-hydrochloricacid, and extracted with ethyl acetate. The extracts were dried,filtrated and concentrated. The residue was purified by silica gelcolumn chromatography (hexane-ethyl acetate=5:1) to obtain a titlecompound (3.87 g, yield 93%).

Oil

¹H-NMR (CDCl₃) δ: 1.28 (3H, t, J=7.5 Hz), 2.73 (2H, q, J=7.5 Hz),7.34-7.50 (2H, m), 7.92-7.98 (2H, m).

Reference Example 4

The following reference example compounds 4-1 and 4-2 were synthesizedaccording to Reference Example 3, using1-bromo-3-(1-methylethyl)benzene, 1-bromo-4-fluoro-3-methylbenzeneinstead of 1-bromo-3-ethylbenzene.

Reference Example Compound 4-1

3-(1-methylethyl)benzoic acid

Oil

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=7.0 Hz), 2.98-3.06 (1H, m), 7.38-7.54(2H, m), 7.90-8.02 (2H, m).

Reference Example Compound 4-2

4-fluoro-3-methylbenzoic acid

m.p. 165-167° C.

Reference Example 5

3-ethylbenzoyl chloride

3-ethylbenzoic acid (9.40 g, 62.6 mmol) was added slowly to thionylchloride (45 mL), and N,N-dimethylformamide (3 drops) was addeddropwise. The resulting reaction mixture was heated under reflux for 2hours under the same condition. The reaction mixture was concentrated,and used in the subsequent reaction without further purification.

Reference Example 6

The following reference example compounds 6-1 to 6-4 were synthesizedaccording to Reference Example 5, using 3-(1-methylethyl)benzoic acid,4-fluoro-3-methylbenzoic acid, 4-cyclohexylbenzoic acid and3,5-dimethylbenzoic acid instead of 3-ethylbenzoic acid.

Reference Example Compound 6-1

3-(1-methylethyl)benzoyl chloride

This was used in the subsequent reaction without purification.

Reference Example Compound 6-2

4-fluoro-3-methylbenzoyl chloride

This was used in the subsequent reaction without purification.

Reference Example Compound 6-3

4-cyclohexylbenzoyl chloride

This was used in the subsequent reaction without purification.

Reference Example Compound 6-4

3,5-dimethylbenzoyl chloride

b.p. 82-85° C. (933 Pa).

Reference Example 7

N-(4-chlorobenzoyl)propyleneimine,

A solution of propyleneimine (12 mL, 0.15 mol) in tetrahydrofuran (160mL) was added to an 1 N-aqueous sodium hydroxide solution. To thismixture was added dropwise 4-chlorobenzoyl chloride (25 g, 0.14 mol) at0° C. After completion of the addition, the mixture was further stirredfor 30 minutes. The reaction mixture was extracted with ethyl acetate.The extract was dried, and the solvent was distilled off to obtain atitle compound (25 g, yield 89%).

Oil

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.5 Hz), 2.15 (1H, d, J=2.9 Hz),2.51-2.66 (2H, m), 7.39-7.47 (2H, m), 7.93-8.01 (2H, m).

Reference Example 8

The following reference example compounds 8-1 to 8-16 were synthesizedaccording to Reference Example 7, using 3-chlorobenzoyl chloride,3-methylbenzoyl chloride, 3,5-dimethylbenzoyl chloride, 4-fluorobenzoylchloride, benzoyl chloride, 3-bromobenzoyl chloride,4-(methylthio)benzoyl chloride, 2-thiophenecarbonyl chloride,3-propylbenzoyl chloride, 3-trifluoromethylbenzoyl chloride,3-ethylbenzoyl chloride, 3-(1-methylethyl)benzoyl chloride,4-fluoro-3-methylbenzoyl chloride, 3-fluorobenzoyl chloride,3-methoxybenzoyl chloride and 4-methoxybenzoyl chloride, respectively,instead of 4-chlorobenzoyl chloride.

Reference Example Compound 8-1

N-(3-chlorobenzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.40 (3H, d, J=5.1 Hz), 2.17 (1H, d, J=3.3 Hz),2.53-2.68 (2H, m), 7.40 (1H, dd, J=7.7, 8.1 Hz), 7.53 (1H, ddd, J=1.5,2.2, 8.1 Hz), 7.90 (1H, dt, J=7.7, 1.5 Hz), 8.00-(1H, dd, J=1.5, 2.2Hz).

Reference Example Compound 8-2

N-(3-methylbenzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.5 Hz), 2.14 (1H, d, J=3.3 Hz), 2.41(3H, s), 2.51-2.66 (2H, m), 7.32-7.39 (2H, m), 7.79-7.87 (2H, m).

Reference Example Compound 8-3

N-(3,5-dimethylbenzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.5 Hz), 2.13 (1H, d, J=3.7 Hz), 2.37(6H, s), 2.47-2.62 (2H, m), 7.19 (1H, s), 7.64 (2H, s).

Reference Example Compound 8-4

N-(4-fluorobenzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.2 Hz), 2.14-2.15 (1H, m), 2.52-2.63(2H, m), 7.08-7.19 (2H, m), 8.00-8.10 (2H, m).

Reference Example Compound 8-5

N-benzoylpropyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.40 (3H, d, J=6.0 Hz), 2.15 (1H, d, J=3.2 Hz),2.52-2.67 (2H, m), 7.40-7.61 (3H, m), 7.98-8.07 (2H, m).

Reference Example Compound 8-6

N-(3-bromobenzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.40 (3H, d, J=5.2 Hz), 2.16-2.18 (1H, m), 2.53-2.65(2H, m), 7.34 (1H, t, J=7.9 Hz), 7.65-7.71 (1H, m), 7.95 (1H, d, J=7.9Hz), 8.16 (1H, t, J=1.8 Hz).

Reference Example Compound 8-7

N-[4-(methylthio)benzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.49 (3H, d, J=6.0 Hz), 2.13 (1H, d, J=3.2 Hz),2.49-2.60 (5H, m), 7.24-7.30 (2H, m), 7.90-7.96 (2H, m).

Reference Example Compound 8-8

N-(2-thiophenecarbonyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.43 (3H, d, J=5.2 Hz), 2.14 (1H, d, J=3.6 Hz),2.56-2.72 (2H, m), 7.08-7.16 (1H, m), 7.53-7.60 (1H, m), 7.75-7.81 (1H,m).

Reference Example Compound 8-9

N-(3-propylbenzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 0.95 (3H, t, J=7.3 Hz), 1.40 (3H, d, J=4.8 Hz),1.59-1.78 (2H, m), 2.14 (1H, d, J=2.8 Hz), 2.52-2.74 (4H, m), 7.34-7.43(2H, m), 7.81-7.89 (2H, m).

Reference Example Compound 8-10

N-(3-trifluoromethylbenzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.42 (3H, d, J=5.5 Hz), 2.20 (1H, d, J=3.3 Hz),2.56-2.67 (2H, m), 7.61 (1H, t, J=7.7 Hz), 7.81 (1H, d, J=7.7 Hz), 8.21(1H, d, J=7.7 Hz), 8.30 (1H, s).

Reference Example Compound 8-11

N-(3-ethylbenzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.27 (3H, t, J=7.5 Hz), 1.40 (3H, d, J=5.5 Hz), 2.14(1H, d, J=2.9 Hz), 2.52-2.61 (2H, m), 2.71 (2H, q, J=7.5 Hz), 7.32-7.41(2H, m), 7.81-7.89 (2H, m).

Reference Example Compound 8-12

N-[3-(1-methylethyl)benzoyl]propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.29 (6H, t, J=7.0 Hz), 1.40 (3H, d, J=5.9 Hz), 2.14(1H, d, J=3.7 Hz), 2.51-2.64 (2H, m), 2.87-3.10 (1H, m), 7.33-7.46 (2H,m), 7.84 (1H, dt, J=7.0, 1.8 Hz). 7.91 (1H, s).

Reference Example Compound 8-13

N-(4-fluoro-3-methylbenzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.4 Hz), 2.14 (1H, d, J=3.4 Hz), 2.33(3H, s), 2.51-2.61 (2H, m), 7.06 (1H, t, J=8.8 Hz), 7.81-7.90 (2H, m).

Reference Example Compound 8-14

N-(3-fluorobenzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.40 (3H, d, J=5.5 Hz), 2.16 (1H, d, J=3.3 Hz),2.52-2.68 (2H, m), 7.25 (1H, ddd, J=1.1, 2.6, 8.4 Hz), 7.43 (1H, ddd,J=5.5, 7.7, 8.1 Hz), 7.69 (1H, ddd, J=1.5, 2.6, 8.1 Hz), 7.81 (1H, ddd,J=1.1, 1.5, 7.7 Hz).

Reference Example Compound 8-15

N-(3-methoxybenzoyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.40 (3H, d, J=5.9 Hz), 2.14 (1H, d, J=2.9 Hz),2.52-2.65 (2H, m), 3.86 (3H, s), 7.10 (1H, ddd, J=1.1, 2.6, 8.4 Hz),7.37 (1H, dd, J=8.4, 7.3 Hz), 7.55 (1H, dd, J=1.5, 2.6 Hz), 7.63 (1H,ddd, J=1.1, 1.5, 7.3 Hz).

Reference Example Compound 8-16

N-(4-methoxyphenyl)propyleneimine,

Oil

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.9 Hz), 2.11 (1H, d, J=3.3 Hz),2.50-2.63 (2H, m), 3.87 (3H, s), 6.94 (2H, d, J=9.2 Hz), 8.00 (1H, d,J=9.2 Hz).

Reference Example 9

2-fluoro-4-methylpyridine

This was synthesized according to a method described in Journal ofMedicinal Chemistry, 33, 1667-1675, 1990.

m.p. 82-86° C. (10 kPa).

Reference Example 10

2-phenylmethyloxy-4-methylpyridine

Sodium hydride (60% paraffin dispersion, 5.0 g, 120 mmol) was washedwith hexane (5 mL) twice, and suspended in tetrahydrofuran (200 mL). Tothis suspension was added dropwise a solution of benzyl alcohol (14 g,120 mol) in tetrahydrofuran (50 mL) at 0° C., and the mixture wasallowed to warm to room temperature and stirred for 15 minutes. To thissolution was added a solution of 2-bromo-4-methylpyridine (20 mL, 110mol) in tetrahydrofuran (50 mL), and the mixture was heated to refluxfor 14 hours. Water (200 mL) was added to the reaction mixture, andextracted with ethyl acetate. The extracted solution was dried, and thesolvent was distilled off. The crude product was distilled under reducedpressure to obtain a title compound (13 g, yield 67%).

b.p. 116-118° C. (400 Pa).

¹H-NMR (CDCl₃) δ: 2.30 (3H, s), 5.37 (2H, s), 6.63 (1H, s), 6.72 (1H, d,J=5.1 Hz), 7.29-7.50 (5H, m), 8.03 (1H, d, J=5.1 Hz).

Reference Example 11

2-tert-butoxycarbonylamino-4-methylpyridine

It was synthesized according to a method described in Synthesis, pp. 877to 882, 1996 or Journal of Organic Chemistry, 61, pp. 4810 to 4811,1996.

Reference Example 12

2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone

Under an argon atmosphere, a solution of diisopropylamine (44 mL, 0.31mol) in anhydrous tetrahydrofuran (300 mL) was cooled to −78° C., and tothis was added dropwise a 1.6 M n-butyllithium hexane solution (190 mL,0.31 mol) with stirring. After completion of the addition, the solutionwas stirred for 10 minutes, subsequently, a solution of2-fluoro-4-methylpyridine (34.5 g, 0.31 mol) in anhydroustetrahydrofuran (30 mL) was added. The reaction mixture was stirred for30 minutes at −10° C. The reaction solution was cooled to −78° C., and asolution of N-(3-methylbenzoyl)propyleneimine (52 g, 0.30 mol) inanhydrous tetrahydrofuran (30 mL) was added dropwise. After completionof the addition, the mixture was stirred for 2 hours at roomtemperature. To the reaction mixture was added water (100 mL), andextracted with ethyl acetate. The extracted solution was washed withwater, dried, then, the solvent was distilled off. The residue wasrecrystallized from isopropyl ether to obtain a title compound (35 g,yield 52%).

m.p. 66-67° C.

Reference Example 13

The following reference example compounds 13-1 to 13-3 were synthesizedaccording to Reference Example 12, usingN-(3-methoxybenzoyl)propyleneimine, N-(4-fluorobenzoyl)propyleneimineand N-(3-chlorobenzoyl)propyleneimine instead ofN-(3-methylbenzoyl)propyleneimine.

Reference Example Compound 13-1

2-(2-fluoro-4-pyridyl)-1-(3-methoxyphenyl)ethanone

Oil

¹H-NMR (CDCl₃) δ: 3.86 (3H, s), 4.31 (2H, s), 6.86 (1H, s), 7.03-7.19(2H, m), 7.31-7.59 (3H, m), 8.18 (1H, d, J=5.6 Hz).

Reference Example Compound 13-2

1-(4-fluorophenyl)-2-(2-fluoro-4-pyridyl)ethanone

m.p. 100-101° C.

Reference Example Compound 13-3

1-(3-chlorophenyl)-2-(2-fluoro-4-pyridyl)ethanone

m.p. 84-86° C.

Reference Example 14

1-(3-methylphenyl)-2-(2-methyl-4-pyridyl)ethanone

A solution of diisopropylamine (112 mL) in anhydrous tetrahydrofuran(760 mL) was cooled to −50° C., and to this was added dropwise a 1.6 Mn-butyllithium hexane solution (500 mL) with stirring. After completionof the addition, the solution was stirred for 10 minutes, subsequently,a solution of 2,4-lutidine (87.9 mL) in anhydrous tetrahydrofuran (76mL) was added dropwise at −30° C. The reaction mixture was stirred for 1hour, then, a solution of N-(3-methylbenzoyl)propyleneimine (134 g) inanhydrous tetrahydrofuran (76 mL) was added dropwise at −78° C. Aftercompletion of the addition, the mixture was stirred for 2 hours at −78°C. The reaction mixture was allowed to warm to room temperature, to thiswas added water (800 mL), and extracted with ethyl acetate. The extractswere washed with water, dried, then, the solvent was distilled off. Theresulted residue was crystallized from isopropyl ether-hexane to obtaina title compound (156 g, yield 91%).

m.p. 56-57° C.

Reference Example 15

The following reference example compounds 15-1 and 15-2 were synthesizedaccording to Reference Example 14, usingN-(3,5-dimethylbenzoyl)propyleneimine andN-(4-fluorobenzoyl)propyleneimine instead ofN-(3-methylbenzoyl)propyleneimine.

Reference Example Compound 15-1

1-(3,5-dimethylphenyl)-2-(2-methyl-4-pyridyl)ethanone

Oil

¹H-NMR (CDCl₃) δ: 2.38 (6H, s), 2.54 (3H, s), 4.21 (2H, s), 6.98-7.10(1H, m), 7.01 (1H, m), 7.06 (1H, s), 7.23 (1H, s), 7.60 (2H, s),8.42-8.45 (1H, m).

Reference Example Compound 15-2

2-(2-methyl-4-pyridyl)-1-(4-fluorophenyl)ethanone

m.p. 79-81° C.

Reference Example 16

The following reference example compounds 16-1 and 16-2 were synthesizedaccording to Reference Examples 14 and 15, using γ-choline instead of2,4-lutidine.

Reference Example Compound 16-1

2-(2,6-dimethyl-4-pyridyl)-1-(3-methylphenyl)ethanone

m.p. 46-48° C.

Reference Example Compound 16-2

1-(3,5-dimethylphenyl)-2-(2,6-dimethyl-4-pyridyl)ethanone

m.p. 135-136° C.

Reference Example 17

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone

A solution of 2-tert-butoxycarbonylamino-4-methylpyridine (20 g, 97mmol) in anhydrous tetrahydrofuran (300 mL) was cooled to −78° C., andto this was added dropwise a 1.6 M n-butyllithium hexane solution (140mL, 0.23 mol) with stirring. After completion of the addition, thesolution was stirred for 30 minutes at 0° C., then, the solution wascooled to −78° C. A solution of N-(4-methoxybenzoyl)propyleneimine (25g, 0.13 mol) in anhydrous tetrahydrofuran (50 mL) was added dropwise.After completion of the addition, the reaction mixture was stirred for 2hours at room temperature. To the reaction mixture was added water (100mL) and isopropyl ether (300 mL), and the resulted crude crystal wasfiltrated. This crude crystal was recrystallized fromtetrahydrofuran-hexane to obtain a title compound (23 g, yield: 69%).

m.p. 187-190° C.

Reference Example 18

The following reference example compounds 18-1 to 18-15 were synthesizedaccording to Reference Example 17, usingN-(3-methylbenzoyl)propyleneimine,N-(3,5-dimethylbenzoyl)propyleneimine,N-(3-chlorobenzoyl)propyleneimine, N-benzoylpropyleneimine,N-(4-fluorobenzoyl)propyleneimine,N-[3-(trifluoromethyl)benzoyl]propyleneimine,N-(3-bromobenzoyl)propyleneimine,N-[4-(methylthio)benzoyl]propyleneimine,N-(2-thiophenecarbonyl)propyleneimine,N-(3-propylbenzoyl)propyleneimine,N-[3-(1-methylethyl)benzoyl]propyleneimine,N-(4-fluoro-3-methylbenzoyl)propyleneimine,N-(3-fluorobenzoyl)propyleneimine, N-(4-chlorobenzoyl)propyleneimine andN-(3-ethylbenzoyl)propyleneimine instead ofN-(4-methoxybenzoyl)propyleneimine.

Reference Example Compound 18-1

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone

m.p. 144-146° C.

Reference Example Compound 18-2

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone

m.p. 133-136° C.

Reference Example Compound 18-3

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-chlorophenyl)ethanone

m.p. 152-153° C.

Reference Example Compound 18-4

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-phenylethanone

m.p. 162-163° C.

Reference Example Compound 18-5

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-fluorophenyl)ethanone

m.p. 139-141° C.

Reference Example Compound 18-6

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-[3-(trifluoromethyl)phenyl]ethanone

m.p. 149-150° C.

Reference Example Compound 18-7

1-(3-bromophenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone

m.p. 132-133° C.

Reference Example Compound 18-8

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-[4-(methylthio)phenyl]ethanone

m.p. 177-178° C.

Reference Example Compound 18-9

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(2-thienyl)ethanone

m.p. 161-162° C.

Reference Example Compound 18-10

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-propylphenyl)ethanone

m.p. 110-111° C.

Reference Example Compound 18-11

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-[(1-methylethyl)phenyl]ethanone

m.p. 176-177° C.

Reference Example Compound 18-12

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-fluoro-3-methylphenyl)ethanone

m.p. 143-144° C.

Reference Example Compound 18-13

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-fluorophenyl)ethanone

m.p. 164-165° C.

Reference Example Compound 18-14

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-chlorophenyl)ethanone

m.p. 155-156° C.

Reference Example Compound 18-15

2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-ethylphenyl)ethanone

m.p. 122-123° C.

Reference Example 19

1-(3,5-dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanone

A solution of diisopropylamine (9.6 mL, 69 mmol) in anhydroustetrahydrofuran (60 mL) was cooled to −50° C., and to this was addeddropwise a 1.6 M n-butyllithium hexane solution (43 mL, 69 mmol) withstirring. After completion of the addition, the solution was stirred for10 minutes, subsequently, a solution of2-phenylmethyloxy-4-methylpyridine (12 g, 62 mmol) in anhydroustetrahydrofuran (12 mL) was dropped at −30° C. After stirring for 1hour, a solution of N-(3,5-dimethylbenzoyl)propyleneimine (12 g, 62mmol) in anhydrous tetrahydrofuran (12 mL) was added dropwise at −30° C.After completion of the addition, the mixture was allowed to warm toroom temperature gradually, and stirred for 2 hours. Water (60 mL) wasadded to the reaction mixture, and extracted with ethyl acetate. Theextracted solution was washed with water, dried, then, the solvent wasdistilled off. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate=5:1) to obtain a title compound(9.1 g, yield 44%).

Oil

¹H-NMR (CDCl₃) δ: 2.37 (6H, s), 4.20 (2H, s), 5.37 (2H, s), 6.72 (1H,s), 6.81 (1H, d, J=5.1 Hz), 7.22 (1H, s), 7.30-7.49 (5H, m), 7.59 (2H,s), 8.12 (1H, d, J=5.1 Hz).

Reference Example 20

2-bromo-2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanonehydrobromide

To a solution of2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone(0.36 g, 1.1 mmol) in acetic acid (5 mL) was added bromine (0.058 mL,1.1 mmol), and the mixture was stirred for 1 hour at room temperature.The reaction mixture was concentrated, and the residue was washed withisopropyl ether to obtain a title compound (0.44 g, yield 82%).

Amorphous.

¹H-NMR (CDCl₃) δ: 1.55 (6H, s), 3.92 (3H, s), 6.35 (1H, s) , 6.99-7.03(2H, m) , 7.66 (1H, dd, J=6:6, 1.8 Hz), 8.02-8.07 (2H, m), 8.20 (1H, d,J=6.6 Hz), 8.70 (2H, d, J=1.8 Hz), 11.02 (1H, br s).

Reference Example 21

The following reference example compounds 21-1 to 21-4 were synthesizedaccording to Reference Example 20, using2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone,1-(3,5-dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanone and1-(3-bromophenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone,respectively, instead of2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone.

Reference Example Compound 21-1

2-bromo-2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanonehydrobromide

This was used in the subsequent reaction without purification.

Reference Example Compound 21-2

2-bromo-2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanonehydrobromide

This was used in the subsequent reaction without purification.

Reference Example Compound 21-3

2-bromo-1-(3,5-dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanonehydrobromide

m.p. 88 to 90° C.

Reference Example Compound 21-4

2-bromo-1-(3-bromophenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanonehydrobromide

This was used in the subsequent reaction without purification.

Reference Example 22

2-bromo-1-(3-methylphenyl)-2-(2-methyl-4-pyridyl)ethanone hydrobromide

1-(3-methylphenyl)-2-(2-methyl-4-pyridyl)ethanone (150 g) was dissolvedin acetic acid (450 mL), bromine (34.3 mL) was added to this, and themixture was stirred for 3 hours at 70° C. The reaction solution wascooled by ice water, and the deposited crystal was filtrated off. Thecrystal was washed with ethyl acetate to obtain a title compound (168 g,yield 66%).

m.p. 144-146° C.

Reference Example 23

The following reference example compounds 23-1 to 23-22 were synthesizedaccording to Reference Example 22, using2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone,2-(2-fluoro-4-pyridyl)-1-(3-methoxyphenyl)ethanone,2-(2-fluoro-4-pyridyl)-1-(4-fluorophenyl)ethanone,2-(2-fluoro-4-pyridyl)-1-(3-chlorophenyl)ethanone,1-(3,5-dimethylphenyl)-2-(2-methyl-4-pyridyl)ethanone,2-(2-methyl-4-pyridyl)-1-(4-fluorophenyl)ethanone,2-(2,6-dimethyl-4-pyridyl)-1-(3-methylphenyl)ethanone,1-(3,5-dimethylphenyl)-2-(2,6-dimethyl-4-pyridyl)ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-chlorophenyl)ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-phenylethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-fluorophenyl)ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-[3-(trifluoromethyl)phenyl]ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-bromophenyl)ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-[4-(methylthio)phenyl]ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(2-thienyl)ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-propylphenyl)ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-[(1-methylethyl)phenyl]ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-fluorophenyl)ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-chlorophenyl)ethanone,2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-ethylphenyl)ethanone and2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-fluoro-3-methylphenyl)ethanone,respectively, instead of1-(3-methylphenyl)-2-(2-methyl-4-pyridyl)ethanone.

Reference Example Compound 23-1

2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide

This was used in the subsequent reaction without purification.

Reference Example Compound 23-2

2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methoxyphenyl)ethanone hydrobromide

This was used in the subsequent reaction without purification.

Reference Example Compound 23-3

2-bromo-2-(2-fluoro-4-pyridyl)-1-(4-fluorophenyl)ethanone hydrobromide

Amorphous

¹H-NMR (DMSO-d₆) δ: 7.16 (1H, s), 7.37-7.54 (4H, m), 8.11-8.24 (2H, m),8.30 (1H, d, J=5.0 Hz).

Reference Example Compound 23-4

2-bromo-1-(3-chlorophenyl)-2-(2-fluoro-4-pyridyl)ethanone hydrobromide

Amorphous

¹H-NMR (DMSO-d₆) δ: 7.19 (1H, s), 7.38 (1H, s), 7.52-7.56 (1H, m), 7.64(1H, t, J=8.0 Hz), 7.77-7.82 (1H, m), 8.05-8.09 (1H, m), 8.16 (1H, t,J=1.8 Hz), 8.32 (1H, d, J=5.2 Hz), 10.23 (1H, br s).

Reference Example Compound 23-5

2-bromo-1-(3,5-dimethylphenyl)-2-(2-methyl-4-pyridyl)ethanonehydrobromide

This was used in the subsequent reaction without purification.

Reference Example Compound 23-6

2-bromo-1-(4-fluorophenyl)-2-(2-methyl-4-pyridyl)ethanone hydrobromide

Amorphous

¹H-NMR (DMSO-d₆) δ: 3.02 (3H, s), 6.68 (1H, s), 7.23 (2H, t, J=8.4 Hz),8.05 (1H, s), 8.10-8.22 (3H, m), 8.65 (1H, br s).

Reference Example Compound 23-7

2-bromo-2-(2,6-dimethyl-4-pyridyl)-1-(3-methylphenyl)ethanonehydrobromide

This was used in the subsequent reaction without purification.

Reference Example Compound 23-8

2-bromo-1-(3,5-dimethylphenyl)-2-(2,6-dimethyl-4-pyridyl)ethanonehydrobromide

m.p. 208-212° C.

Reference Example Compound 23-9

2-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone hydrobromide

m.p. 182-185° C.

Reference Example Compound 23-10

2-(2-amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)ethanone hydrobromide

m.p. 199-200° C.

Reference Example Compound 23-11

2-(2-amino-4-pyridyl)-2-bromo-1-phenylethanone hydrobromide

m.p. 155-156° C.

Reference Example Compound 23-12

2-(2-amino-4-pyridyl)-2-bromo-1-(4-fluorophenyl)ethanone hydrobromide

m.p. 171-172° C.

Reference Example Compound 23-13

2-(2-amino-4-pyridyl)-2-bromo-1-[3-(trifluoromethyl)phenyl]ethanonehydrobromide

m.p. 174-175° C.

Reference Example Compound 23-14

2-(2-amino-4-pyridyl)-2-bromo-1-(3-bromophenyl)ethanone hydrobromide

This was used in the subsequent reaction without purification.

Reference Example Compound 23-15

2-(2-amino-4-pyridyl)-2-bromo-1-[4-(methylthio)phenyl]ethanonehydrobromide

Amorphous

¹H-NMR (DMSO-d₆) δ: 6.96-7.09 (2H, m), 7.24 (1H, s), 7.32-7.43 (1H, m),7.98 (1H, d, J=6.6 Hz), 8.12-8.36 (2H, m).

Reference Example Compound 23-16

2-(2-amino-4-pyridyl)-2-bromo-1-(2-thienyl)ethanone hydrobromide

Amorphous

¹H-NMR (DMSO-d₆) δ: 2.57 (3H, s), 6.94-7.01 (1H, m), 7.14 (1H, s), 7.21(1H, s), 7.38-7.46 (2H, m), 7.83-8.06 (3H, m), 8.21 (2H, br).

Reference Example Compound 23-17

2-(2-amino-4-pyridyl)-2-bromo-1-(3-propylphenyl)ethanone hydrobromide

Amorphous

¹H-NMR (DMSO-d₆) δ: 0.90 (3H, t, J=7.3 Hz), 1.53-1.73 (2H, m), 2.65 (2H,t, J=7.5 Hz), 3.40-(2H, br s), 6.97 (1H, dd, J=1.8, 6.6 Hz), 7.13 (1H,s), 7.19 (1H, s), 7.46-7.59 (2H, m), 7.89-7.99 (3H, m), 8.14 (1H, br d,J=6.6 Hz).

Reference Example Compound 23-18

2-(2-amino-4-pyridyl)-2-bromo-1-[3-(1-methylethyl)phenyl]ethanonehydrobromide

Amorphous

¹H-NMR (DMSO-d₆) δ: 1.24 (6H, d, J=6.6 Hz), 3.00 (1H, septet, J=6.6 Hz),7.15 (1H, s), 7.17 (1H, s), 7.46-7.65 (2H, m), 7.88-7.98 (4H, m), 8.09(1H, br s).

Reference Example Compound 23-19

2-(2-amino-4-pyridyl)-2-bromo-1-(3-fluorophenyl)ethanone hydrobromide

m.p. 206-207° C.

Reference Example Compound 23-20

2-(2-amino-4-pyridyl)-2-bromo-1-(4-chlorophenyl)ethanone hydrobromide

m.p. 202-203° C.

Reference Example Compound 23-21

2-(2-amino-4-pyridyl)-2-bromo-1-(3-ethylphenyl)ethanone hydrobromide

m.p. 46-47° C.

Reference Example Compound 23-22

2-(2-amino-4-pyridyl)-2-bromo-1-(4-fluoro-3-methylphenyl)ethanonehydrobromide

m.p. 225-226° C.

Reference Example 24

4-(methylthio)thiobenzamide

4-(methylthio)benzonitrile (12 g, 80 mmol) was dissolved in a solutionof 4 N hydrogen chloride in ethyl acetate (130 mL). To this solution wasadded dithiophosphoric acid 0,0-diethyl ester(15 mL, 88 mmol), and themixture was stirred for 22 hours at room temperature. Water (100 mL) wasadded to the reaction mixture, and extracted with ethyl acetate. Theinsoluble material was filtrated off, then, the filtrate was washed withbrine, dried, then, the solvent was distilled off. The residue wasrecrystallized from ethyl acetate to obtain a title compound (10 g,yield 67%).

m.p. 176-178° C.

Reference Example 25

The following reference example compounds 25-1 to 25-10 were synthesizedaccording to Reference Example 24, using 2-chlorobenzonitrile,4-chlorobenzonitrile, 2-fluorobenzonitrile, 4-fluorobenzonitrile,2,4-difluorobenzonitrile, butyronitrile, valeronitrile,3-phenylpropionitrile, 4-phenylbutyronitrile,1-methylpiperidine-4-carbonitrile, respectively, instead of4-(methylthio)benzonitrile.

Reference Example Compound 25-1

2-chlorothiobenzamide

m.p. 58-59° C.

Reference Example Compound 25-2

4-chlorothiobenzamide

m.p. 130-131° C.

Reference Example Compound 25-3

2-fluorothiobenzamide

m.p. 113-114° C.

Reference Example Compound 25-4

4-fluorothiobenzamide

m.p. 156-157° C.

Reference Example Compound 25-5

2,4-difluorothiobenzamide

m.p. 127-128° C.

Reference Example Compound 25-6

thiobutyramide

Oil

¹H-NMR (CDCl₃) δ: 0.99 (3H, t, J=7.6 Hz), 1.72-1.93 (2H, m), 2.64 (2H,t, J=7.6 Hz), 7.02 (1H, br s), 7.77 (1H, br s).

Reference Example Compound 25-7

thiovaleramide

Oil

¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.3 Hz), 1.31-1.49 (2H, m), 1.68-1.83(2H, m), 2.67 (2H, t, J=7.7 Hz), 6.92 (1H, br s), 7.73 (1H, br s).

Reference Example Compound 25-8

3-phenyl(thiopropionamide)

m.p. 83-84° C.

Reference Example Compound 25-9

4-phenyl(thiobutyramide)

m.p. 60-61° C.

Reference Example Compound 25-10

1-methylpiperidine-4-carbothioamide

m.p. 216-220° C.

Reference Example 26

ethyl (4-phenyl-1-piperazinyl)carbothioylcarbamate

To a solution of ethyl isothiocyanatoformate (8.1 g, 62 mmol) in acetone(30 mL) was added 1-phenylpiperazine (10 g, 62 mmol), and the mixturewas heated to reflux for 1 hour. The reaction mixture was concentrated,and the crude crystal was recrystallized from ethyl acetate to obtain atitle compound (13 g, yield 73%).

m.p. 134-135° C.

Reference Example 27

The following reference example compound 27 was synthesized according toReference Example 26 using 1-methylpiperazine instead of1-phenylpiperazine.

Reference Example Compound 27

ethyl (4-methyl-piperazinyl)carbothioylcarbamate

m.p. 155-157° C.

Reference Example 28

4-phenyl-1-piperazinecarbothioamide

Ethyl (4-phenyl-1-piperazinyl)carbothioylcarbamate (13 g, 44 mmol) wasadded to conc. hydrochloric acid (44 mL), and the mixture was stirredfor 2 hours at 80° C. The reaction mixture was made basic with an8N-aqueous sodium hydroxide solution, and the crystal was collected byfiltration. The crystal was washed with water, and dried to obtain atitle compound (6.1 g, yield 63%).

m.p. 178-179° C.

Reference Example 29

The following reference example compound 29 was synthesized according toReference Example 28 using ethyl(4-methyl-1-piperazinyl)carbothioylcarbamate instead of ethyl(4-phenyl-1-piperazinyl)carbothioylcarbamate.

Reference Example Compound 29

4-methyl-1-piperazinecarbothioamide

m.p. 173-175° C.

Reference Example 30

3,3,3-trifluorothiopropionamide

To a solution of 3,3,3-trifluoropropionamide (2.00 g, 15.7 mmol) inanhydrous tetrahydrofuran (100 mL) was added a Lawesson's reagent (3.79g, 9.37 mmol), and the mixture was heated under reflux for 2 hours. Themixture was cooled to room temperature, then, an aqueous saturatedsodium hydrogen carbonate solution was added to the reaction mixture,and extracted with ethyl acetate. The extracts were dried, to distilloff the solvent. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate=10:1 to 4:1) to give a titlecompound (1.85 g, yield: 82%).

Oil

¹H-NMR (CDCl₃) δ: 3.61 (2H, q, J=10.4 Hz), 6.70-8.00 (2H, m).

Reference Example 31

The following reference example compounds 31-1 and 31-2 were synthesizedaccording to Reference Example 30, using ethyl 3-amino-3-oxopropanateand ethyl 2-amino-2-oxoacetate instead of 3,3,3-trifluoropropionamide.

Reference Example Compound 31-1

ethyl 3-amino-3-thioxopropanate

Oil

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J=7.1 Hz), 3.85 (2H, s), 4.22 (2H, q,J=7.1 Hz), 7.74 (1H, br s), 8.92 (1H, br s).

Reference Example Compound 31-2

ethyl 2-amino-2-thioxoacetate

¹H-NMR (CDCl₃) δ: 1.41 (3H, t, J=7.2 Hz), 4.38 (2H, q, J=7.2 Hz), 7:68(1H, br s), 8.24 (1H, br s).

Reference Example 32

The following reference example compound 32 was synthesized according toExample 33 described later, using4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-5-(4-pyridyl)-1,3-thiazoleinstead of4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole.

Reference Example Compound 32

4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]pyridineN-oxide

m.p. 196-197° C.

Reference Example 33

1-tert-butoxycarbonylpiperidine-4-carboxamide

To a solution of piperidine-4-carboxamide (5.0 g, 39 mmol) in water (30mL) was added di-tert-butyl dicarbonate (9.2 mL, 40 mmol) slowly, andthen the reaction mixture was stirred at room temperature for 24 hours.The resulting mixture was extracted with ethyl acetate, and the extractswere washed with brine, dried, and concentrated in vacuo. The residuewas crystallized from ethyl acetate to give a title compound (6.9 g,yield 78%).

m.p. 163-165° C.

Reference Example 34

The following reference example compound 34 was synthesized according toReference example 30, using1-tert-butoxycarbonylpiperidine-4-carboxamide instead of3,3,3-trifluoropropionamide.

Reference Example Compound 34

1-tert-butoxycarbonylpiperidine-4-carbothioamide

m.p. 129-131° C.

Reference Example 35

The following reference example compound 35 was synthesized according toReference example 12, using N-(3-ethylbenzoyl)propyleneimine instead ofN-(3-methylbenzoyl)propyleneimine

Reference Example Compound 35

1-(3-ethylphenyl)-2-(2-fluoro-4-pyridyl)ethanone

m.p. 59-60° C.

Reference Example 36

The following reference example compound 36 was synthesized according toReference example 22, using1-(3-ethylphenyl)-2-(2-fluoro-4-pyridyl)ethanone instead of1-(3-methylphenyl)-2-(2-methyl-4-pyridyl)ethanone

Reference Example Compound 36

2-bromo-1-(3-ethylphenyl)-2-(2-fluoro-4-pyridyl)ethanone hydrobromide

amorphous

¹H-NMR(DMSO-d₆) d: 1.22 (3H, t, J=7.6 Hz), 2.70 (2H, q, J=7.6 Hz), 7.19(1H, s), 7.39 (1H, s), 7.45-7.58 (3H, m), 7.77 (1H, br s), 7.92-7.97(2H, m), 8.30 (1H, d, J=5.6 Hz).

Reference Example 37

ethyl 2,2-difluoropropionate

To ethyl pyruvate (3.0 g, 26 mmol) was added dropwisedimethylaminosulfur trifluoride (3.4 mL, 26 mmol) over 1 hour and thereaction mixture was stirred at 60° C. for 4 hours. The resultingmixture was poured into ice-water and extracted with ethyl acetate. Theextracts were washed with brine, dried, and concentrated under reducedpressure to give a title compound (1.2 g, yield 78%).

Oil

¹H-NMR(CDCl₃) d: 1.36 (3H, t, J=7.2 Hz), 1.81 (3H, t, J=19.0 Hz), 4.33(2H, q, J=7.2 Hz).

Reference Example 38

2,2-difluoropropionic acid

A solution of ethyl 2,2-difluoropropionate (1.2 g, 8.8 mmol) methanol(26 mL) was added to 2N aqueous sodium hydroxide (26 mL) and theresulting mixture was stirred at room temperature for 14 hours. Thereaction mixture was acidified with 2N hydrochloric acid and extractedwith ether. The extracts were dried, and concentrated under reducedpressure to give a title compound (0.90 g, yield 92%).

Oil

¹H-NMR(CDCl₃) d: 1.85 (3H, t, J=19.0 Hz), 6.21 (1H, br s).

Reference Example 39

2,2-difluoropropionamide

To a solution of 2,2-difluoropropionic acid (7.8 g, 71 mmol) intetrahydrofuran (80 mL) was added oxalyl chloride (6.6 mL, 78 mmol) atroom temperature and then N,N-dimethylformamide (2 drops) was added tothe solution. The reaction mixture was stirred at room temperature for 2hours. The resulting solution was added dropwise to 25% aqueous ammoniaat 0° C. over 15 minutes, and stirred for 1 hour. The reaction mixturewas extracted with ethyl acetate. The extracts were dried, andconcentrated under reduced pressure. The obtained crude mixture wascrystallized from hexane to give a title compound (3.7 g, yield 49%).

m.p. 70-71° C.

Reference Example 40

The following reference example compound 40 was synthesized according toReference example 24, using (methylthio)acetonitrile instead of4-(methylthio)benzonitrile.

Reference Example Compound 40

(methylthio)thioacetamide

m.p. 66-67° C.

Reference Example 41

The following reference example compound 41-1 and 41-2 were synthesizedaccording to Reference example 30, using 3-(methylthio)propionamide and2,2-difluoropropionamide instead of 3,3,3-trifluoropropionamide.

Reference Example Compound 41-1

3-(methylthio)thiopropionamide

Oil

¹H-NMR(CDCl₃) d: 2.17 (3H, s), 2.93 (4H, s), 7.52 (2H, br s).

Reference Example Compound 41-2

2,2-difluorothiopropionamide

Oil

¹H-NMR(CDCl₃) d: 1.98 (3H, t, J=18.5 HZ), 7.56 (1H, br s), 7.72 (1H, brs).

Reference Example 42

2-amino-1-methyl-2-oxoethyl benzoate

To a solution of 2-hydroxypropionamide (10.8 g, 121 mmol) in pyridine(40 mL) was added benzoyl chloride (14.2 mL, 122 mmol) at 0° C. and thereaction mixture was allowed to warm up to room temperature. Theresulting mixture was stirred at room temperature for 3 hours and thesolvent was removed under reduced pressure to give a residue. To theresidue an aqueous sodium hydrogen carbonate solution was added and themixture was extracted with ethyl acetate. The extracts were washed withan 1N hydrochloric acid twice and brine. The organic solution was dried,and concentrated under reduced pressure. The obtained crude crystal wasrecrystallized from ethyl acetate-hexane to give a title compound (17.9g, yield 77%).

m.p. 116-117° C.

Reference Example 43

2-amino-1-methyl-2-thioxoethyl benzoate

To a solution of 2-amino-1-methyl-2-oxoethyl benzoate (10.0 g, 52.0mmol) in 1,2-dimethoxyethane (90 mL) was added Lawesson's reagent (11.2g, 27.7 mmol) at 0° C. and the reaction mixture was allowed to warm upto room temperature. The resulting mixture was stirred at roomtemperature for 24 hours and the precipitate was removed by filtration.The resulting solution was concentrated under reduced pressure to give aresidue. The residue was dissolved in ethyl acetate and the solution waswashed with brine. The organic solution was dried, and concentratedunder reduced pressure to give a residue. The residue was purified bysilica gel column chromatography (hexane-ethyl acetate=2:1) to obtain acrude crystal. The crude crystal was recrystallized from ethylacetate-hexane to give a title compound (8.60 g, yield 79%).

m.p. 100-101° C.

Example 1

[5-(2-amino-4-pyridyl)-4-(4-methoxyphenyl)-1,3-thiazol-2-yl]amine

To a solution of2-bromo-2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanonehydrobromide (synthesized from2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone(4.5 g, 13 mmol) according to the method described in Reference Example20) in acetonitrile (40 mL) were added thiourea (1.1 g, 14 mmol) andtriethylamine (1.9 mL, 14 mmol), and the mixture was stirred for 2 hoursat 80° C. The reaction mixture was cooled to room temperature, then,concentrated. To the residue was added a saturated aqueous sodiumhydrogen carbonate solution (200 mL), and the resulting solid wasfiltrated, and washed with water. To this solid was added2N-hydrochloric acid (35 mL), and the mixture was stirred for 45 minutesat 100° C. The reaction mixture was cooled to room temperature, then,8N-sodium hydroxide aqueous solution (10 mL) and aqueous sodium hydrogencarbonate solution (100 mL) were added. The resulted crude crystal wasfiltrated, and washed with water. This crude crystal was recrystallizedfrom ethanol to obtain a title compound (2.7 g, yield 69%).

m.p. 251 to 254° C.

Example 2

[5-(2-tert-butoxycarbonylamino-4-pyridyl)-3-(4-methoxyphenyl)-1,3-thiazol-2-yl]amine

To a solution of2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone(6.1 g, 18 mmol) in acetic acid (100 mL) was added bromine (1.0 mL), andthe mixture was stirred for 2 hours at room temperature. The reactionmixture was concentrated. The residue was dissolved in acetonitrile (100mL), and to this solution were added thiourea (1.1 g, 14 mmol) andtriethylamine (3.0 mL, 22 mmol), and the mixture was stirred at roomtemperature for 2 hours, then, concentrated. To the residue was added asaturated aqueous sodium hydrogen carbonate solution (50 mL), and theresulted solid was filtrated, washed with water, and recrystallized fromethanol to give a title compound (1.7 g, yield: 24%).

m.p. 270° C. or more (dec.)

Example 3

[5-(2-tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-4-(3-methylphenyl)-1,3-thiazole

A solution of2-bromo-2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanonehydrobromide (synthesized from2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone (5.0g, 24 mmol) according to the method described in Reference Example 21)and thiopropionamide (1.4 g, 16 mmol) in N,N-dimethylformamide (50 mL)was stirred for 14 hours at room temperature. To the reaction mixturewas poured an aqueous sodium hydrogen carbonate solution, and extractedwith ethyl acetate. The extracts were washed with water, then, dried andconcentrated. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate=4:1) to obtain a crystal. Thiscrystal was washed with hexane to obtain a title compound (2.43 g, yield39%).

m.p. 162-163° C.

Example 4

The following example compounds 4-1 and 4-2 were synthesized accordingto Example 3, using thioacetamide and 4-(methylthio)thiobenzamideinstead of thiopropionamide.

Example Compound 4-1

5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-methyl-4-(3-methylphenyl)-1,3-thiazole

This was used in the subsequent reaction without purification.

Example Compound 4-2

[5-[2-(tert-butoxycarbonylamino)-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole

This was used in the subsequent reaction without purification.

Example 5

The following example compound 5 was synthesized according to Example 4,using2-bromo-2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanonehydrobromide instead of2-bromo-2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanonehydrobromide.

Example Compound 5

5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-4-(4-methoxyphenyl)-2-methyl-1,3-thiazole

This was used in the subsequent reaction without purification.

Example 6

[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine

To a mixture of2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromideand thiourea (3.03 g, 39.8 mmol) in acetonitrile (50 mL) was addedtriethylamine (5.2 mL, 37.3 mmol), and the mixture was stirred for 2hours at 80° C. Aqueous sodium hydrogen carbonate solution was pouredinto the reaction mixture, and the deposited solid was collected byfiltration. The resulted solid was washed with water, then, dried. Thecrude crystal was recrystallized from ethanol to obtain a title compound(3.67 g, yield 35%).

m.p. 214-218° C.

Example 7

The following example compounds 7-1 to 7-8 were synthesized according toExample 6, using2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methoxyphenyl)ethanone hydrobromide,2-bromo-1-(3-chlorophenyl)-2-(2-fluoro-4-pyridyl)ethanone hydrobromide,2-bromo-1-(4-fluorophenyl)-2-(2-fluoro-4-pyridyl)ethanone hydrobromide,2-bromo-1-(3-methylphenyl)-2-(2-methyl-4-pyridyl)ethanone hydrobromide,2-bromo-1-(3,5-dimethylphenyl)-2-(2-methyl-4-pyridyl)ethanonehydrobromide,2-bromo-1-(3,5-dimethylphenyl)-2-(2,6-dimethyl-4-pyridyl)ethanonehydrobromide and2-bromo-1-(3,5-dimethylphenyl)-2-(2,6-dimethyl-4-pyridyl)ethanonehydrobromide, 2-bromo-1-(4-fluorophenyl)-2-(2-methyl-4-pyridyl)ethanonehydrobromide, respectively, instead of2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide.

Example Compound 7-1

[5-(2-fluoro-4-pyridyl)-4-(3-methoxyphenyl)-1,3-thiazol-2-yl]amine

m.p. 190-191° C.

Example Compound 7-2

4-(3-chlorophenyl)-5-(2-fluoro-4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 227-228° C.

Example Compound 7-3

[4-(4-fluorophenyl)-5-(2-fluoro-4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 243-245° C.

Example Compound 7-4

[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 205-206° C.

Example Compound 7-5

[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 219-220° C.

Example Compound 7-6

[5-(2,6-dimethyl-4-pyridyl)-3-(3-methylphenyl)-1,3-thiazol-2-yl]amine

m.p. 214-216° C.

Example Compound 7-7

[4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 256-258° C.

Example Compound 7-8

[4-(4-fluorophenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 233-234° C.

Example 8

The following example compound 8 was synthesized according to Example 6,using N-methylthiourea instead of thiourea.

Example Compound 8

N-methyl-[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine

m.p. 186-187° C.

Example 9

The following example compound 9 was synthesized according to Example 8,using 2-bromo-2-(2-methyl-4-pyridyl)-1-(3-methylphenyl)ethanonehydrobromide instead of2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide.

Example Compound 9

N-methyl-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 164-165° C.

Example 10

The following example compound 10 was synthesized according to Example9, using N,N-dimethylthiourea instead of N-methylthiourea.

Example Compound 10

N,N-dimethyl-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 77-79° C.

Example 11

2-ethyl-5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole

A solution of 2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanonehydrobromide (11 g, 29 mmol) and thiopropionamide (2.7 g, 30 mmol) inN,N-dimethylformamide (30 mL) was stirred for 14 hours at roomtemperature. Aqueous sodium hydrogen carbonate solution was added to thereaction mixture, and extracted with ethyl acetate. The extracts werewashed with water, dried, then, the solvent was distilled off. Theresidue was purified by silica gel column chromatography (hexane-ethylacetate=4:1) to obtain a title compound (3.3 g, yield 38%).

Oil

¹H-NMR (CDCl₃) δ: 1.64 (3H, t, J=7.6 Hz), 2.34 (3H, s), 3.10 (2H, q,J=7.6 Hz), 6.84-6.86 (1H, m), 7.05-7.09 (1H, m), 7.13-7.25 (3H, m), 7.37(1H, s), 8.10 (1H, d, J=5.6 Hz).

Example 12

The following example compound 12 was synthesized according to Example11, using 2-bromo-1-(3-chlorophenyl)-2-(2-fluoro-4-pyridyl)ethanonehydrobromide instead of2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide.

Example Compound 12

2-ethyl-4-(3-chlorophenyl)-5-(2-fluoro-4-pyridyl)-1,3-thiazole

m.p. 102-103° C.

Example 13

The following example compound 13 was synthesized according to Example11, using 2-bromo-1-(3-methylphenyl)-2-(2-methyl-4-pyridyl)ethanonehydrobromide instead of2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide.

Example Compound 13

2-ethyl-4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazole

Oil

¹H-NMR (CDCl₃) δ: 1.45 (3H, t, J=7.6 Hz), 2.33 (3H, s), 2.51 (3H, s),3.09 (2H, q, J=7.6 Hz), 6.99 (1H, dd, J=1.2, 5.2 Hz), 7.13-7,30 (4H, m),7.39 (1H, s), 8.38 (1H, d, J=5.2 Hz).

Example 14

The following example compounds 14-1 to 14-14 were synthesized accordingto Example 13, using 2-chlorothiobenzamide, 4-chlorothiobenzamide,2-fluorothiobenzamide, 4-fluorothiobenzamide, 2,4-difluorothiobenzamide,thiobenzamide, phenyl(thioacetamide), 3-phenyl(thiopropionamide),4-phenyl(thiobutyramide), thiovaleramide, thiobutyramide, ethyl2-amino-2-thioxoacetate, 4-methyl-1-piperazinecarbothioamide and1-methylpiperidine-4-carbothioamide, respectively, instead ofthiopropionamide.

Example Compound 14-1

2-(2-chlorophenyl)-4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazole

m.p. 83-84° C.

Example Compound 14-2

2-(4-chlorophenyl)-4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazole

m.p. 104-105° C.

Example Compound 14-3

2-(2-fluorophenyl)-4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazole

m.p. 73-74° C.

Example Compound 14-4

2-(4-fluorophenyl)-4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazole

m.p. 89-91° C.

Example Compound 14-5

2-(2,4-difluorophenyl)-4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazole

m.p. 90-91° C.

Example Compound 14-6

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-phenyl-1,3-thiazole

m.p. 79-80° C.

Example Compound 14-7

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-(phenylmethyl)-1,3-thiazole

m.p. 82-84° C.

Example Compound 14-8

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-(2-phenylethyl)-1,3-thiazole

m.p. 64-65° C.

Example Compound 14-9

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-(3-phenylpropyl)-1,3-thiazole

Oil

¹H-NMR (CDCl₃) δ: 2.12-2.27 (2H, m), 2.33 (3H, s), 2.50 (3H, s), 2.79(2H, t, J=7.7 Hz), 3.08 (2H, t, J=7.9 Hz), 6.98 (1H, dd, J=1.4, 5.6 Hz),7.10-7.35 (9H, m), 7.38 (1H, s), 8.38 (1H, d, J=5.6 Hz).

Example Compound 14-10

2-butyl-4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazole

Oil

¹H-NMR (CDCl₃) δ: 0.99 (3H, t, J=7.1 Hz), 1.43-1.56 (2H, m), 1.76-1.91(2H, m), 2.33 (3H, s), 2.50 (3H, s), 3.05 (2H, t, J=7.9 Hz), 6.99 (1H,d, J=5.4 Hz), 7.10-7.20 (4H, m), 7.38 (1H, s), 8.37 (1H, d, J=5.4 Hz).

Example Compound 14-11

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-propyl-1,3-thiazole

Oil

¹H-NMR (CDCl₃) δ: 1.08 (3H, t, J=7.4 Hz), 1.79-2.00 (2H, m), 2.33 (3H,s), 2.50 (3H, s), 3.03 (2H, t, J=7.4 Hz), 6.99 (1H, d, J=5.3 Hz),7.10-7.20 (4H, m), 7.39 (1H, s), 8.37 (1H, d, J=5.3 Hz).

Example Compound 14-12

Ethyl[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]carboxylate

m.p. 97-98° C.

Example Compound 14-13

4-(3-methylphenyl)-2-(4-methylpiperazin-1-yl)-5-(2-methyl-4-pyridyl)-1,3-thiazole

m.p. 115-116° C.

Example Compound 14-14

4-(3-methylphenyl)-2-(1-methylpiperazin-4-yl)-5-(2-methyl-4-pyridyl)-1,3-thiazole

m.p. 127-130° C.

Example 15

The following example compound 15 was synthesized according to Example11, using 4-(methylthio)thiobenzamide, instead of thiopropionamide.

Example Compound 15

5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole

m.p. 97-100° C.

Example 16

The following example compounds 16-1 to 16-6 were synthesized accordingto Example 15, using2-bromo-1-(3-methylphenyl)-2-(2-methyl-4-pyridyl)ethanone hydrobromide,2-bromo-1-(3,5-dimethylphenyl)-2-(2-methyl-4-pyridyl)ethanonehydrobromide, 2-bromo-1-(3,5-dimethylphenyl)-2-(2,6-dimethyl-4-pyridyl)ethanone hydrobromide,2-bromo-1-(3,5-dimethylphenyl)-2-(2,6-dimethyl-4-pyridyl)ethanonehydrobromide, 2-bromo-1-(4-fluorophenyl)-2-(2-methyl-4-pyridyl)ethanonehydrobromide and2-(2-amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)ethanone hydrobromide,respectively, instead of2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide.

Example Compound 16-1

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole

m.p. 119-122° C.

Example Compound 16-2

4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole

m.p. 123-125° C.

Example Compound 16-3

5-(2,6-dimethyl-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole

m.p. 112-114° C.

Example Compound 16-4

4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole

m.p. 134-136° C.

Example Compound 16-5

4-(4-fluorophenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole

m.p. 99-100° C.

Example Compound 16-6

4-[4-(3-chlorophenyl)-2-[4-(methylthio)phenyl-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 183-184° C.

Example 17

4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

A solution of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanonehydrobromide (5.00 g, 12.3 mmol) and 2-chlorothiobenzamide (1.06 g, 11.9mmol) in N,N-dimethylformamide (40 mL) was stirred for 14 hours at roomtemperature. Aqueous sodium hydrogen carbonate solution was poured intothe reaction mixture, and extracted with ethyl acetate. The extractswere washed with water, dried, and concentrated. The residue waspurified by silica gel column chromatography (hexaneethyl acetate=4:1 to2:1) to obtain a crystal. This crystal was washed with isopropyl ether,to obtain a title compound (3.15 g, yield 81%).

m.p. 175-177° C.

Example 18

The following example compounds 18-1 to 18-6 were synthesized accordingto Example 17, using 4-fluorothiobenzamide, thiovaleramide,3,3,3-trifluorothiopropionamide, thiobutyramide, ethyl3-amino-3-thioxopropanate, ethyl 2-amino-2-thioxoacetate, respectively,instead of 2-chlorothiobenzamide.

Example Compound 18-1

4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 160-162° C.

Example Compound 18-2

4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

Oil

¹H-NMR (CDCl₃) δ: 0.98 (3H, t, J=7.3 Hz), 1.39-1.59 (2H, m), 1.76-1.92(2H, m), 2.34 (3H, s), 3.04 (2H, t, J=7.4 Hz), 4.14 (2H, br s), 6.44(1H, s), 6.56 (1H, dd, J=1.5, 5.4 Hz), 7.09-7.26 (3H, m), 7.41 (1H, s),7.96 (1H, d, J=5.4 Hz).

Example Compound 18-3

4-[4-(3-methylphenyl)-2-(2,2,2-trifluoroethyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 131-132° C.

Example Compound 18-4

4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 113-115° C.

Example Compound 18-5

Ethyl [5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]acetate

m.p. 128-129° C.

Example Compound 18-6

Ethyl[5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]carboxylate

m.p. 147-148° C.

Example 19

The following example compound 22 was synthesized according to Example17, using thiopropionamide instead of 2-chlorothiobenzamide.

Example 20

The following example compounds 20-1 to 20-12 were synthesized accordingto Example 19, using2-(2-amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)ethanone hydrobromide,2-(2-amino-4-pyridyl)-2-bromo-1-phenylethanone hydrobromide,2-(2-amino-4-pyridyl)-2-bromo-1-(4-fluorophenyl)ethanone hydrobromide,2-(2-amino-4-pyridyl)-2-bromo-1-[3-(trifluoromethyl)phenyl]ethanonehydrobromide,2-(2-amino-4-pyridyl)-2-bromo-1-[4-(methylthio)phenyl]ethanonehydrobromide, 2-(2-amino-4-pyridyl)-2-bromo-1-(3-fluorophenyl)ethanone (hydrobromide, 2-(2-amino-4-pyridyl)-2-bromo-1-(4-chlorophenyl)ethanonehydrobromide, 2-(2-amino-4-pyridyl)-2-bromo-1-(3-ethylphenyl)ethanonehydrobromide,2-(2-amino-4-pyridyl)-2-bromo-1-(4-fluoro-3-methylphenyl)ethanonehydrobromide,2-(2-amino-4-pyridyl)-2-bromo-1-[3-(1-methylethyl)phenyl]ethanonehydrobromide, 2-(2-amino-4-pyridyl)-2-bromo-1-(3-propylphenyl)ethanonehydrobromide, 2-(2-amino-4-pyridyl)-2-bromo-1-(2-thienyl)ethanonehydrobromide, respectively, instead of2-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone hydrobromide.

Example Compound 20-1

4-[2-ethyl-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 132-133° C.

Example Compound 20-2

4-(2-ethyl-4-phenyl-1,3-thiazol-5-yl)-2-pyridylamine

m.p. 158-159° C.

Example Compound 20-3

4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 140-141° C.

Example Compound 20-4

4-[2-ethyl-4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 117-118° C.

Example Compound 20-5

4-[2-ethyl-4-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 119-120° C.

Example Compound 20-6

4-[2-ethyl-4-(3-fluorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 153-154° C.

Example Compound 20-7

4-[4-(4-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 136-137° C.

Example Compound 20-8

4-[2-ethyl-4-(3-ethylphenyl)-1,3-thiazol-5-yl]2-pyridylamine

m.p. 128-129° C.

Example Compound 20-9

4-[2-ethyl-4-(4-fluoro-3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 134-135° C.

Example Compound 20-10

4-[2-ethyl-4-[3-(1-methylethyl)phenyl]-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 80-81° C.

Example Compound 20-11

4-[2-ethyl-4-(3-propylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 72-74° C.

Example Compound 20-12

4-[2-ethyl-4-(2-thienyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 159-160° C.

Example 21

The following example compounds 21-1 and 21-2 were synthesized accordingto Example 18, using2-(2-amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)ethanone hydrobromideinstead of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanonehydrobromide.

Example Compound 21-1

4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 99-100° C.

Example Compound 21-2

Ethyl [5-(2-amino-4-pyridyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]acetate

m.p. 154-155° C.

Example 22

4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

To5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-4-(3-methylphenyl)-1,3-thiazole(synthesized from2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone (35g, 170 mmol) according to the method described in Example 3) was added2N-hydrochloric acid (200 mL), and the mixture was stirred for 1 hour at100° C. The reaction mixture was cooled to room temperature, then, madealkaline with a 2N aqueous sodium hydrogen carbonate solution (200 mL)and aqueous sodium hydrogen carbonate solution. The resulted mixture wasextracted by ethyl acetate, and the extracts were washed with water.This extracts were dried and concentrated. The residue was purified bysilica gel column chromatography (hexane-ethyl acetate=1:1) to obtain acrystal. This crystal was washed with isopropyl ether, to obtain a titlecompound (17 g, yield 55%).

m.p. 144-146° C.

Example 23

The following example compounds 23-1 to 23-3 were synthesized accordingto Example 22, using5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-methyl-4-(3-methylphenyl)-1,3-thiazole,5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazoleand5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-4-(4-methoxyphenyl)-2-methyl-1,3-thiazole,respectively, instead of5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-4-(3-methylphenyl)-1,3-thiazole.

Example Compound 23-1

4-[2-methyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 152-153° C.

Example Compound 23-2

4-[4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 181-183° C.

Example Compound 23-3

4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 140-141° C.

Example 24

[5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]acetic acid

To a suspension of ethyl[5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]acetate (7.00g, 19.8 mmol) in ethanol (40 mL) was added a 1N aqueous sodium hydroxidesolution (40 mL), and the mixture was stirred for 2 hours at the roomtemperature under the same condition, The reaction mixture wasneutralized with 2N hydrochloric acid (20 mL), then, the produced solidwas collected by filtration. The crude product was washed with water,and dried to obtain a title compound (6.10 g, yield: 95%).

m.p. 132-133° C.

Example 25

The following example compounds 25-1 to 25-3 were synthesized accordingto Example 24, using ethyl[5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]carboxylate,ethyl[5-(2-methyl-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]carboxylateand ethyl[5-(2-amino-4-pyridyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]acetate,respectively, instead of ethyl[5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]acetate.

Example Compound 25-1

5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole-2-carboxylic acid

m.p. 156-157° C.

Example Compound 25-2

5-(2-methyl-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole-2-carboxylic acid

m.p. 135-136° C.

Example Compound 25-3

[5-(2-methyl-4-pyridyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]acetic acid

This was used in the subsequent reaction without purification.

Example 26

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazole

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazole-2-carboxylic acid(0.20 g, 0.64 mmol) was stirred for 15 minutes at 150° C. It was cooledto room temperature, then, the crude product was purified by silica gelcolumn chromatography (ethyl acetate) to obtain a title compound (0.17g, yield 98%).

Oil

¹H-NMR (CDCl₃) δ: 2.34 (3H, s), 2.53 (3H, s), 7.04 (1H, d, J=5.1 Hz),7.16-7.24 (4H, m), 7.43 (1H, s), 8.42 (1H, d, J=5.1 Hz), 8.88 (1H, s).

Example 27

The following example compounds 27-1 and 27-2 were synthesized accordingto Example 26, using5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole-2-carboxylic acidand [5-(2-amino-4-pyridyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]aceticacid.

Example Compound 27-1

4-[4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 91-92° C.

Example Compound 27-2

4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 142-143° C.

Example 28

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]cyclohexanecarboxamide

To a solution of4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.80 g,2.7 mmol) in tetrahydrofuran (10 mL) were added cyclohexanecarbonylchloride (0.40 mL, 3.0 mmol) and triethylamine (0.39 mL, 2.8 mmol)sequentially, and the mixture was stirred for 1 hour at roomtemperature. To the reaction mixture was added an aqueous sodiumhydrogen carbonate solution, and extracted with ethyl acetate. Theextracts were washed with an aqueous sodium hydrogen carbonate solution,then, dried and concentrated. The residue was purified by silica gelcolumn chromatography (hexane-ethyl acetate=20:1 to 4:1) to obtain acrystal. This crystal was washed with hexane to obtain a title compound(0.83 g, yield 75%).

m.p. 98-100° C.

Example 29

The following example compounds 29-1 to 29-5 were synthesized accordingto Example 28, using cyclopentanecarbonyl chloride, acetyl chloride,1-methylcyclohexanecarbonyl chloride, propionyl chloride and pivaloylchloride instead of cyclohexanecarbonyl chloride.

Example Compound 29-1

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]cyclopentanecarboxamide

m.p. 123-125° C.

Example Compound 29-2

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 119-120° C.

Example Compound 29-3

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-1-methylcyclohexanecarboxamide

Oil

¹H-NMR (CDCl₃) δ: 1.28 (3H, s), 1,30-1.75 (11H, m), 1.98-2.12 (2H, m),2,33 (3H, s), 3.08 (2H, q, J=7.6 Hz), 6.79-6.85 (1H, m), 7.10-7.25 (3H,m), 7.38-7.42 (1H, m), 8.04-8.07 (2H, m), 8.40-8.43 (1H, m).

Example Compound 29-4

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 103-104° C.

Example Compound 29-5

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]pivalamide

Oil

¹H-NMR (CDCl₃) δ: 1.34 (9H, s), 1.44 (3H, t, J=7.6 Hz), 2.33 (3H, s) ,3.08 (2H, q, J=7.6 Hz), 6.79-6.84 (1H, m), 7.09-7.27 (3H, m), 7.36-7.39(1H, m), 8.03-8.10 (2H, m), 8.38-8.42 (1H, m).

Example 30

The following example compounds 30-1 to 30-12 were synthesized accordingto Example 29, using4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridylamine,4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridylamine,4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(2-thienyl)-1,3-thiazol-5-yl]-2-pyridylamine and4-[4-(3-chlorophenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridylamine,respectively, instead of4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine.

Example Compound 30-1

N-[4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 112-115° C.

Example Compound 30-2

N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 149-150° C.

Example Compound 30-3

N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 144-145° C.

Example Compound 30-4

N-[4-[2-ethyl-4-(2-thienyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 154-155° C.

Example Compound 30-5

N-[4-[4-(3-chlorophenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 207-208° C.

Example Compound 30-6

N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]-1-methylcyclohexanecarboxamide

Oil

¹H-NMR (CDCl₃) δ: 1.28 (3H, s), 1.35-1.82 (11H, m), 1.95-2.13 (2H, m),3.08 (2H, q, J=7.8 Hz), 6.80-6.84 (1H, m), 7.19-7,37 (3H, m), 7.53-7.62(1H, m), 8.07-8.12 (1H, m), 8.25-8.35 (1H, m), 8.40-8.43 (1H, m).

Example Compound 30-7

N-[4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide.

m.p. 134-135° C.

Example Compound 30-8

N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 132-133° C.

Example Compound 30-9

N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 103-104° C.

Example Compound 30-10

N-[4-[2-ethyl-4-(2-thienyl)-1,3-thiazol-5-yl]2-pyridyl]propionamide

m.p. 187-188° C.

Example Compound 30-11

N-[4-[4-(3-chlorophenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 187-188° C.

Example Compound 30-12

N-[4-[4-(3-chlorophenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridyl]pivalamide

m.p. 119-120° C.

Example 31

N-(cyclohexylmethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

To a solution of aluminum chloride (0.40 g, 3.0 mmol) in tetrahydrofuran(40 mL) was added lithium aluminum hydride (0.12 g, 3.0 mmol) at 0° C.To this solution was added dropwise a solution ofN-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]cyclohexanecarboxamine(0.40 g, 0.99 mmol) in tetrahydrofuran (10 mL), and the mixture washeated under reflux for 1 hour. The reaction mixture was cooled to roomtemperature, to this was added ice water, and extracted with ethylacetate. The extracts were washed with an aqueous sodium hydrogencarbonate solution, then, dried and concentrated. The residue waspurified by silica gel column chromatography (hexane-ethyl acetate=20:1to 4:1) to obtain a crystal. This crystal was washed with hexane toobtain a title compound (0.27 g, yield 70%).

m.p. 74-75° C.

Example 32

The following example compound 32 was synthesized according to Example31, usingN-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]cyclopentanecarboxamineinstead ofN-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]cyclohexanecarboxamine.

Example Compound 32

N-(cyclopentylmethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 67-69° C.

Example 33

[4-(3-methylphenyl)-5-(2-pyperidino-4-pyridyl)-1,3-thiazol-2-yl]amine

5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.70g, 2.5 mmol) and piperidine (2.0 mL, 20 mmol) were stirred at 150° C.for 3 hours. The reaction mixture was purified by silica gel columnchromatography (hexane-ethyl acetate=1:1) to obtain a title compound(0.62 g, yield 72%).

m.p. 181-182° C.

Example 34

The following example compounds 34-1 to 34-3 were synthesized accordingto Example 33, using morpholine, cyclohexylamine and cyclopentylamineinstead of piperidine.

Example Compound 34-1

[4-(3-methylphenyl)-5-(2-morpholino-4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 188-189° C.

Example Compound 34-2

[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine

m.p. 168-169° C.

Example Compound 34-3

[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine

m.p. 169-170° C.

Example 35

The following example compounds 35-1 and 35-2 were synthesized accordingto Example 34, using4-(3-chlorophenyl)-5-(2-fluoro-4-pyridyl)-1,3-thiazol-2-yl]amine and5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazoleinstead of5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine

Example Compound 35-1

[4-(3-chlorophenyl)-5-(2-piperidino-4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 206-208° C.

Example Compound 35-2

4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-5-(2-piperidino-1-pyridyl)-1,3-thiazole

m.p. 155-157° C.

Example 36

The following example compounds 36-1 to 36-11 were synthesized accordingto Example 34, using5-(2-fluoro-4-pyridyl)-4-(4-fluorophenyl)-1,3-thiazol-2-yl]amine,N-methyl-[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,2-ethyl-5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole,5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazoleand 4-(3-chlorophenyl)-2-ethyl-5-(2-fluoro-4-pyridyl)-1,3-thiazole,respectively, instead of5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine.

Example Compound 36-1

[5-(2-cyclohexylamino-4-pyridyl)-4-(4-fluorophenyl)-1,3-thiazol-2-yl]amine

m.p. 194-195° C.

Example Compound 36-2

N-methyl-[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine

m.p. 211-212° C.

Example Compound 36-3

N-methyl-[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine

m.p. 170-172° C.

Example Compound 36-4

N-cyclohexyl-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 110-112° C.

Example Compound 36-5

N-cyclohexyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 197-199° C.

Example Compound 36-6

N-cyclopentyl-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 117-118° C.

Example Compound 36-7

N-cyclopentyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 154-156° C.

Example Compound 36-8

4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-5-(2-morpholino-4-pyridyl)-1,3-thiazole

m.p. 200-202° C.

Example Compound 36-9

2-ethyl-4-(3-methylphenyl)-5-(2-morpholino-4-pyridyl)-1,3-thiazole

m.p. 69-71° C.

Example Compound 36-10

4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclohexyl-2-pyridylamine

m.p. 106-107° C.

Example Compound 36-11

4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclopentyl-2-pyridylamine

m.p. 110-111° C.

Example 37

The following example compounds 37-1 to 37-5 were synthesized accordingto Example 36, using pyrrolidine, N-methylcyclohexylamine,(cyclohexylmethyl)amine and 1-methylpiperazine, respectively, instead ofcyclohexylamine.

Example Compound 37-1

2-ethyl-4-(3-methylphenyl)-5-[2-(1-pyrrolidinyl)-4-pyridyl]-1,3-thiazole

m.p. 108-109° C.

Example Compound 37-2

N-cyclohexyl-N-methyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 173-174° C.

Example Compound 37-3

N-cyclohexylmethyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 157-159° C.

Example Compound 37-4

4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-5-[2-(1-pyrrolidinyl)-4-pyridyl]-1,3-thiazole

m.p. 199-201° C.

Example Compound 37-5

4-(3-methylphenyl)-5-[2-(4-methyl-1-piperazinyl)-4-pyridyl]-2-(4-methylsulfonylphenyl)-1,3-thiazole

m.p. 153-154° C.

Example 38

N-[5-(2-acetylamino-4-pyridyl)-4-(4-methoxyphenyl)-1,3-thiazol-2-yl]acetamide

To a solution of4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.40 g,1.4 mmol) and 4-dimethylaminopyridine (0.055 g, 0.45 mmol) inN,N-dimethylacetamide (10 mL) was added acetyl chloride (0.3 mL, 4.2mmol), and the mixture was stirred for 14 hours at 70° C. An aqueoussodium hydrogen carbonate solution was poured into the reaction mixture,and extracted with ethyl acetate. The extracts were washed with brine,then, dried and concentrated. The crude crystal was recrystallized fromethanol to obtain a title compound (0.30 g, yield 58%).

m.p. 262-264° C.

Example 39

N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]acetamide

To a solution of[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine (0.50g, 1.8 mmol) and 4-dimethylaminopyridine (0.061 g, 0.50 mmol) inN,N-dimethylacetamide (15 mL) was added acetyl chloride (0.19 mL, 2.7mmol), and the mixture was stirred for 14 hours at 80° C. An aqueoussodium hydrogen carbonate solution was poured into the reaction mixture,and the deposited solid was filtrated. The resulted solid was washedwith water, then, dried. The crude crystal was recrystallized fromethanol, to obtain a title compound (0.39 g, yield 67%).

m.p. 230-231° C.

Example 40

The following example compounds 40-1 to 40-3 were synthesized accordingto Example 39, using[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine,[5-(2,6-dimethyl-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amineand[4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-1,3-thiazol-2-yl]amine,respectively, instead of[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine.

Example Compound 40-1

N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]acetamide

m.p. 236-237° C.

Example Compound 40-2

N-[5-(2,6-dimethyl-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]acetamide

m.p. 185-187° C.

Example Compound 40-3

N-[4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-1,3-thiazol-2-yl]acetamide

m.p. 266-267° C.

Example 41

The following example compound 41 was synthesized according to Example39, using nicotinoyl chloride hydrochloride instead of acetyl chloride.

Example Compound 41

N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 175-178° C.

Example 42

The following example compounds 42-1 to 42-10 were synthesized accordingto Example 41, using[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine,[4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-1,3-thiazol-2-yl]amine,[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,[5-(2-cyclopentylamin-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,[5-(2-cyclohexylamino-4-pyridyl)-4-(4-fluorophenyl)-1,3-thiazol-2-yl]amine,[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,[4-(4-fluorophenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine,N-[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-N-methylamine,N-[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-N-methylamineandN-methyl-N-[5-(2-methyl-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,respectively, instead of[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine.

Example Compound 42-1

N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 203-206° C.

Example Compound 42-2

N-[4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 267-268° C.

Example Compound 42-3

N-[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 201-203° C.

Example Compound 42-4

N-[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 215-216° C.

Example Compound 42-5

N-[5-(2-cyclohexylamino-4-pyridyl)-4-(4-fluorophenyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 136-138° C.

Example Compound 42-6

N-[(5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 229-231° C.

Example Compound 42-7

N-[4-(4-fluorophenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 261-262° C.

Example Compound 42-8

N-[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-N-methylnicotinamide

m.p. 147-148° C.

Example Compound 42-9

N-[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]N-methylnicotinamide

m.p. 148-148° C.

Example Compound 42-10

N-methyl-N-[5-(2-methyl-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide

Oil

¹H-NMR (CDCl₃) δ: 2.35 (3H, s), 2.53 (3H, s), 3,78 (3H, s), 7.05 (1H, d,J=5.2 Hz), 7.06-7.30 (4H, m), 7.41 (1H, s), 7.49 (1H, dd, J=5.2, 7.0Hz), 7.95 (1H, d, J=7,0 Hz), 8,40 (1H, d, J=5.2 Hz), 8.80 (1H, d, J=5.2Hz), 8.88 (1H, s).

Example 43

The following example compound 43 was synthesized according to Example39 using 6-chloro-3-pyridylcarbonyl chloride hydrochloride instead ofacetyl chloride.

Example Compound 43

6-chloro-N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 228-230° C.

Example 44

The following example compounds 44-1 to 44-4 were synthesized accordingto Example 43, using[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amineandN-methyl-[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,respectively, instead of[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine.

Example Compound 44-1

6-chloro-N-[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 255-256° C.

Example Compound 44-2

6-chloro-N-[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 211-212° C.

Example Compound 44-3

6-chloro-N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 271-273° C.

Example Compound 44-4

6-chloro-N-[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-N-methylnicotinamide

m.p. 171-172° C.

Example 45

The following example compound 45 was synthesized according to Example39, using 6-methyl-3-pyridylcarbonyl chloride hydrochloride instead ofacetyl chloride.

Example Compound 45

6-methyl-N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 233-234° C.

Example 46

The following example compounds 46-1 to 46-4 were synthesized accordingto Example 45, using[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amineandN-methyl-[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,respectively, instead of[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine.

Example Compound 46-1

N-[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-6-methylnicotinamide

m.p. 242-243° C.

Example Compound 46-2

N-[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-6-methylnicotinamide

m.p. 213-214° C.

Example Compound 46-3

N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-6-methylnicotinamide

m.p. 252-253° C.

Example Compound 46-4

N-[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-N,6-dimethylnicotinamide

m.p. 117-118° C.

Example 47

The following example compound 47 was synthesized according to Example39, using 6-methoxy-3-pyridylcarbonyl chloride hydrochloride instead ofacetyl chloride.

Example Compound 47

6-methoxy-N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 224-226° C.

Example 48

The following example compounds 48-1 and 48-3 were synthesized accordingto Example 47, using[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amineand[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine,respectively, instead of[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine.

Example Compound 48-1

N-[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-6-methoxynicotinamide

m.p. 191-192° C.

Example Compound 48-2

N-[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-6-methoxynicotinamide

m.p. 219-221° C.

Example Compound 48-3

N-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-6-methoxynicotinamide

m.p. 242-244° C.

Example 49

The following example compound 49 was synthesized according to Example39, using 2-methoxy-3-pyridylcarbonyl chloride hydrochloride instead ofacetyl chloride.

Example Compound 49

2-methoxy-N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide

m.p. 169-170° C.

Example 50

The following example compound 50 was synthesized according to Example39, using[5-(2-tert-butoxycarbonylamino-4-pyridyl)-3-(4-methoxyphenyl)-1,3-thiazol-2-yl]amineinstead of[4-(3-methylphenyl)-5-(2-methyl-1-pyridyl)-1,3-thiazol-2-yl]amine.

Example Compound 50

N-[5-(2-amino-4-pyridyl)-4-(4-methoxyphenyl)-1,3-thiazol-2-yl]acetamide

m.p. 247-250° C.

Example 51

The following example compound 51 was synthesized according to Example50, using benzoyl chloride instead of acetyl chloride.

Example Compound 51

N-[5-(2-amino-4-pyridyl)-4-(4-methoxyphenyl)-1,3-thiazol-2-yl]benzamide

m.p. 219-222° C.

Example 52

N-[4-(2,6-dimethyl-4-pyridyl)-5-(3-methylphenyl)-1,3-thiazol-2-yl]-N′-phenylurea

To a solution of[4-(2,6-dimethyl-4-pyridyl)-5-(3-methylphenyl)-1,3-thiazol-2-yl]amine(0.50 g, 1.7 mmol) in N,N-dimethylacetamide (20 mL) was added phenylisocyanate (0.28 mL, 2.6 mmol), and the mixture was stirred for 14 hoursat 80° C. Aqueous sodium hydrogen carbonate was poured into the reactionmixture, and extracted with ethyl acetate. The extracts were washed withbrine, then, dried to be concentrated. The residue was purified bysilica gel column chromatography (hexane-ethyl acetate=1:1). Theresulted crude crystal was recrystallized from ethyl acetate-hexane toobtain a title compound (0.34 g, yield 48%).

m.p. 173-174° C.

Example 53

The following example compounds 53-1 to 53-4 were synthesized accordingto Example 52, using[4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-1,3-thiazol-2-yl]amine,[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amineand [4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine,respectively, instead of[4-(2,6-dimethyl-4-pyridyl)-5-(3-methylphenyl)-1,3-thiazol-2-yl]amine.

Example Compound 53-1

N-[4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-1,3-thiazol-2-yl]-N′-phenylurea

m.p. 219-222° C.

Example Compound 53-2

N-[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-N′-phenylurea

m.p. 198-199° C.

Example Compound 53-3

N-[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-N′-phenylurea

m.p. 188-190° C.

Example Compound 53-4

N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-N′-phenylurea

m.p. 168-169° C.

Example 54

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-(4-methylsulfinylphenyl)-1,3-thiazole

To a solution of4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole(0.55 g, 1.4 mmol) in acetic acid (15 mL) was added a solution ofpotassium persulfate (0.43 g, 1.6 mmol) in water (8 mL), and the mixturewas stirred for 14 hours at room temperature. An aqueous sodium hydrogencarbonate solution was poured into the reaction mixture, and extractedwith ethyl acetate. The extracts were washed with water, dried, then,the solvent was distilled off. The residue was purified by columnchromatography (filler: Chromatorex NH DM1020 (trade name, manufacturedby Fuji Silysia Chemical Ltd.), hexane-ethyl acetate=1:4), andrecrystallized from ethyl acetate-hexane to obtain a title compound(0.15 g, yield 26%).

m.p. 128-130° C.

Example 55

5-(2,6-dimethyl-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfinylphenyl)-1,3-thiazole

To a solution of5-(2,6-dimethyl-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole(0.41 g, 1.0 mmol) in N,N-dimethylformamide (15 mL) was addedm-chloroperbenzoic acid (0.25 g, 1.0 mmol), and the mixture was stirredfor 1 hour at room temperature. A 8N aqueous sodium hydroxide solutionwas poured into the reaction mixture, and extracted with ethyl acetate.The extracted solution was washed with brine, dried, then, the solventwas distilled off. The residue was purified by column chromatography(filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji SilysiaChemical Lte.), hexane-ethyl acetate=1:2), to obtain a title compound(0.41 g, yield 97%).

m.p. 133-134° C.

Example 56

The following example compounds 56-1 and 56-2 were synthesized accordingto Example 55, using4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazoleand4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazoleinstead of instead of5-(2,6-dimethyl-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole

Example Compound 56-1

4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-2-(4-methylsulfinylphenyl)-1,3-thiazole

m.p. 151-153° C.

Example Compound 56-2

4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-2-(4-methylsulfinylphenyl)-1,3-thiazole

m.p. 151-154° C.

Example 57

4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole

To a solution of4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole(0.61 g, 1.6 mmol) in N,N-dimethylformamide (15 mL) was addedm-chloroperbenzoic acid (0.87 g, 3.6 mmol), and the mixture was stirredfor 30 minutes at room temperature. An aqueous sodium hydrogen carbonatesolution was poured into the reaction mixture, and extracted with ethylacetate. The extracts were washed with water, dried, then, the solventwas distilled off. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate=1:1), and recrystallized fromethanol to obtain a title compound (0.39 g, yield 59%).

m.p. 134-138° C.

Example 58

The following example compounds 58-1 to 58-8 were synthesized accordingto Example 57, using4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole,5-(2,6-dimethyl-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole,4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole,5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole,4-(4-fluoropheyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole,N-[4-[4-(3-chlorophenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridyl]acetamide,N-[4-[4-(3-chlorophenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridyl]propionamideandN-[4-[4-(3-chlorophenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridyl]pivalamide.

Example Compound 58-1

4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole,

m.p. 196-197° C.

Example Compound 58-2

5-(2,6-dimethyl-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole,

m.p. 182-184° C.

Example Compound 58-3

4-(3,5-dimethylphenyl)-5-(2,6-dimethyl-4-pyridyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole,

m.p. 217-220° C.

Example Compound 58-4

5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole,

m.p. 195-199° C.

Example Compound 58-5

4-(4-fluorophenyl)-5-(2-methyl-4-pyridyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole,

m.p. 190-192° C.

Example Compound 58-6

N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide,

m.p. 216-217° C.

Example Compound 58-7

N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide,

m.p. 224-225° C.

Example Compound 58-8

N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]pivalamide,

m.p. 122-123° C.

Example 59

4-[4-(3,5-dimethylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-methylpyridineN-oxide

To a solution of4-[4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole(0.60 g, 1.5 mmol) in N,N-dimethylformamide (20 mL) was addedm-chloroperbenzoic acid (0.80 g, 3.2 mmol), and the mixture was stirredfor 30 minutes at room temperature. m-Chloroperbenzoic acid (0.11 g,0.45 mmol) was added to the reaction mixture, and the mixture wasfurther stirred for 20 minutes at room temperature. m-Chloroperbenzoicacid (0.38 g, 1.5 mmol) was added to the reaction mixture, and themixture was further stirred for 20 minutes at room temperature. Anaqueous sodium hydrogen carbonate solution was poured, and extractedwith ethyl acetate. The extracts were washed with water, dried, then,the solvent was distilled off. The residue was purified by silica gelcolumn chromatography (hexane-ethyl acetate=1:4), and recrystallizedfrom ethanol to obtain a title compound (0.30 g, yield 44%).

m.p. 255-256° C.

Example 60

N-[4-[4-(3-chlorophenyl)-2-(1-methylpiperidin-4-yl)-1,3-thiazol-5-yl]-2-pyridyl]propionamidedihydrochloride

To a solution ofN-[4-[4-(3-chlorophenyl)-2-(4-piperidyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide(0.31 g, 0.72 mmol) in N,N-dimethylformamide (8 mL) were added potassiumcarbonate (0.11 g, 0.82 mmol) and methyl iodide (0.045 mL, 0.72 mmol)were added sequentially, and stirred at room temperature for 20 hours.Aqueous sodium hydrogen carbonate was added to the reaction mixture andextracted with ethyl acetate. The extracts were washed with brine,dried, and concentrated. The residue was purified by columnchromatography (filler: Chromatorex NH DM1020 (trade name, manufacturedby Fuji Silysia Chemical Ltd.), hexane-ethyl acetate=1:1) and treatedwith 10% solution of hydrogen chloride in methanol to obtainhydrochloride. The crude crystalline was washed with ethyl acetate togive a title compound (0.12 g, yield 32%).

m.p. 248-253° C.

Example 61

The following example compound 61 was synthesized according to Example53, using 2-chloroethyl isocyanate instead of phenyl isocyanate.

Example Compound 61

N-(2-chloroethyl)-N′-[5-(2-methyl-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]urea

m.p. 149-151° C.

Example 62

The following example compound 62 was synthesized according to Example39, using 2-chloroethyl chloroformate instead of acetyl chloride

Example Compound 62

2-chloroethyl[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]carbamate

m.p. 156-158° C.

Example 63

N-methoxy-N′-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]urea

To a solution of[4-(2-methyl-4-pyridyl)-3-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.50g, 1.8 mmol) in N,N-dimethylacetamide (20 mL) was added1,1-carbonyldiimidazole (0.43 g, 2.7 mmol), and the mixture was stirredfor 3 hours at room temperature. A 0-methylhydroxylamine hydrochloride(0.22 g, 2,7 mmol) was added to the reaction mixture, and the mixturewas stirred for 24 hours at room temperature. An aqueous sodium hydrogencarbonate solution was poured into the reaction mixture, and theproduced solid was filtrated. This solid was washed with water, anddried. The crude product was purified by column chromatography (filler:Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia ChemicalLtd.), ethyl acetate). The resulted crystal was recrystallized fromethyl acetate to obtain a title compound (0.16 g, yield 25%).

m.p. 194-195° C.

Example 64

The following example compound 64 was synthesized according to Example63, using 0-phenylhydroxylamine hydrochloride instead of0-methylhydroxylamine hydrochloride.

Example Compound 64

N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-N′-phenyloxyurea

m.p. 154-155° C.

Example 65

3-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-5-yl]-oxazolidin-2-one

To a solution of2-chloroethyl[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]carbamate(0.30 g, 0.80 mmol) in N,N-dimethylformamide (3 mL) was added potassiumtert-butoxide (0.12 g, 1.1 mmol), and the mixture was stirred at roomtemperature for 1 hour. An aqueous sodium hydrogen carbonate solutionwas poured into the reaction mixture, and extracted with ethyl acetate.The extracts were washed with water, dried, and concentrated. Theresidue was purified by silica gel column chromatography (hexane-ethylacetate=4:1) to obtain a crystal. This crystal was recrystallized fromhexane-ethyl acetate, to obtain a title compound (0.20 g, yield 72%).

m.p. 80-82° C.

Example 66

The following example compound 66 was synthesized according to Example65, usingN-(2-chloroethyl)-N′-[5-(2-methyl-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]ureainstead of2-chloroethyl[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]carbamate.

Example Compound 66

1-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]imidazolidin-2-one

m.p. 200-201° C.

Example 67

1-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-3-phenylimidazolidin-2-one

To a suspension of1-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]-3-imidazolidin-2-one(0.42 g, 1.2 mmol), copper powder (0.23 g, 3.6 mmol), copper chloride(0.01 g, 0.12 mmol) and potassium acetate (0.23 g, 2.4 mmol) inN,N-dimethylacetamide (10 mL) was added bromobenzene (0.56 g, 3.6 mmol),and the mixture was stirred at 150° C. for 4 hours. After filtration,water was added, and extracted with ethyl acetate. The extracts werewashed with water, then, dried, and concentrated. The residue waspurified by silica gel column chromatography (hexane-ethyl acetate=4:1)to obtain crude crystal. This crude crystal was recrystallized fromethyl acetate, to obtain a title compound (0.18 g, yield 35%).

m.p. 180-182° C.

Example 68

The following example compounds 68-1 and 68-2 were synthesized accordingto Example 59, using4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazoleand 2-ethyl-4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazoleinstead of4-(3,5-dimethylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole.

Example Compound 68-1

4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-methylpyridineN-oxide

m.p. 197-198° C.

Example Compound 68-2

[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-methylpyridine N-oxide

Oil

¹H-NMR (CDCl₃) δ: 1.41 (3H, t, J=7.6 Hz), 2.34 (3H, s), 2.46 (3H, s),3.09 (2H, q, J=7.6 Hz), 7.01 (1H, dd, J=2.2, 7.0 Hz), 7.12-7.24 (4H, m),8.10 (1H, d, J=2.0 Hz).

Example 69

5-(2-chloro-4-pyridyl)-2-ethyl-4-(3-methylphenyl)-1,3-thiazole

A solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]pyridineN-oxide (1.00 g, 3.37 mmol) in phosphorus oxychloride (6.5 mL) wasstirred at 100° C. for 2 hours. The reaction solution was cooled, andpoured into a saturated aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The extracts were washed with brine, then,dried, and concentrated. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate=2:1) to obtain a title compound(0.90 g, yield 81%).

Oil

¹H-NMR (CDCl₃) δ: 1.42 (3H, t, J=7.8 Hz), 2.35 (3H, s), 3.10 (2H, q,J=7.8 Hz), 7.09 (1H, dd, J=1.4, 5.2 Hz), 7.12-7.30 (4H, m), 7.37 (1H,s), 8.22-8.27 (1H, m).

Example 70

A solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]pyridineN-oxide (1.0 g, 3.2 mmol) in phosphorus oxychloride (8 mL) was stirredat 100° C. for 1 hour. The reaction solution was cooled, and poured intoa saturated aqueous sodium hydrogen carbonate solution, and extractedwith ethyl acetate. The extracts were washed with brine, then, dried,and concentrated. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate=10:1 to 2:1) to5-(2-chloro-6-methyl-4-pyridyl)-2-ethyl-4-(3-methylphenyl)-1,3-thiazole(0.60 g, yield 57%) and5-(2-chloromethyl-4-pyridyl)-2-ethyl-4-(3-methylphenyl)-1,3-thiazole(0.20 g, yield 19%).

Example Compound 70-1

5-(2-chloro-6-methyl-4-pyridyl)-2-ethyl-4-(3-methylphenyl)-1,3-thiazole

Oil

¹H-NMR (CDCl₃) δ: 1.45 (3H, t, J=7.8 Hz), 2.35 (3H, s), 2.45 (3H, s),3.09 (2H, q, J=7.8 Hz), 6.98 (1H, s), 7.06 (1H, s), 7.12-7.24 (3H, m),7.38 (1H, s).

Example Compound 70-2

5-(2-chloromethyl-4-pyridyl)-2-ethyl-4-(3-methylphenyl)-1,3-thiazole

Oil

¹H-NMR (CDCl₃) δ: 1.46 (3H, t, J=7.6 Hz), 2.33 (3H, s), 3.10 (2H, q,J=7.6 Hz), 4.59 (2H, s), 7.10-7.23 (4H, m), 7.35-7.40 (2H, m), 8.42-8.47(1H, m).

Example 71

5-(2-cyanomethyl-4-pyridyl)-2-ethyl-4-(3-methylphenyl)-1,3-thiazole

A suspension of5-(2-chloromethyl-4-pyridyl)-2-ethyl-4-(3-methylphenyl)-1,3-thiazole(0.40 g, 1.2 mmol), potassium cyanide (0.095 g, 1.5 mmol), 18-crown-6(0.14 g, 0.51 mmol) in acetonitrile (5 mL) was heated under reflux for 6hours. After cooling, an aqueous potassium carbonate solution was added,and extracted with ethyl acetate. The extracts were washed with brine,then, dried, and concentrated. The residue was purified by silica gelcolumn chromatography (hexane-ethyl acetate=2:1). The resulting crystalwas washed with hexane-isopropyl ether to obtain a title compound (0.19g, 48%).

m.p. 68-69° C.

Example 72

4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylmethanol

To a solution of4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]pyridineN-oxide (0.43 g, 1.0 mmol) in methylene chloride (10 mL) was addedtrimethyloxonium tetrafluoroborate (0.17 g, 1.2 mmol), and the mixturewas stirred for 2 hours. The reaction mixture was concentrated underreduced pressure, and methanol (15 mL) was added to the residue. To themixture was added a solution of ammonium persulfate (0.05 g, 0.22 mmol)in water (1 mL) under reflux, and the mixture was heated to reflux for30 minutes. A solution of ammonium persulfate (0.03 g, 0.11 mmol) inwater. (1 mL) was added to the reaction mixture, and the mixture wasfurther heated to reflux for 13 hours. The reaction mixture was cooledto room temperature, then, concentrated under reduced pressure. To theresidue was added an aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The extracts were washed with brine, driedover magnesium sulfate, and filtrated and concentrated under reducedpressure. The residued was purified by column chromatography (filler:Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia ChemicalLtd.), ethyl acetate) to obtain a title compound (0.26 g, yield 61%).

m.p. 172-173° C.

Example 73

2-(4-methylsulfonylphenyl)-4-(3-methylphenyl)-5-[2-(1-pyrrolidinylmethyl)-4-pyridyl]-1,3-thiazoledihydrochloride

To a solution of4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylmethanol(0.43 g, 1.0 mmol) in tetrahydrofuran (20 mL) was added thionyl chloride(0.08 mL, 1.0 mmol), and the mixture was stirred for 20 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was added to a suspension of pyrrolidine (0.09 mL, 1.1 mmol) andpotassium carbonate (0.36 g, 2.6 mmol) in N,N-dimethylformamide (10 mL),and the mixture was stirred for 27 hours at room temperature. To themixture was added an aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The extracts were washed with brine, driedover magnesium sulfate, and filtrated and concentrated under reducedpressure. The residue was purified by column chromatography (filler:Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia ChemicalLtd.), hexane-ethyl acetate=1:2). The resulted oil was dissolved inmethanol (10 mL), and to this was added a 10% hydrogen chloride-methanolsolution (5 mL), and the mixture was stirred for 1 hour at roomtemperature. The reaction mixture was concentrated under reducedpressure, and the resulting solid was washed with ethanol, to obtain atitle compound (yield 17%).

Amorphous

¹H-NMR (CDCl₃) δ: 1.90-2.10 (4H, m), 2.33 (3H, s), 3.31 (3H, s),4.10-4.40 (4H, m), 4.53 (2H, s), 7.28 (3H, s), 7.43-7.47 (2H, m), 7.67(1H, s), 8.12 (2H, d, J=8.0 Hz), 8.30 (2H, d, J=8.0 Hz), 8.68 (1H, d,J=5.2 Hz).

Example 74

2-ethyl-4-(3-methylphenyl)-5-[2-(1-pyrrolidinylmethyl)-4-pyridyl]-1,3-thiazoledihydrochloride

To a solution of5-(2-chloromethyl-4-pyridyl)-2-ethyl-4-(3-methylphenyl)-1,3-thiazole(0.20 g, 0.61 mmol) in pyrrolidine (0.5 mL) was stirred for 1 hour at80° C. After cooling, to this was added an aqueous potassium carbonatesolution, and extracted with ethyl acetate. The extracts were washedwith brine, then, dried and concentrated. The residue was purified byalumina column chromatography (hexane-ethyl acetate=2:1). The resultingoil was made into a hydrochloride by using a solution of 4N-hydrogenchloride in ethyl acetate, and recrystallized from ethanol-isopropylether, to obtain a title compound (0.23 g, 85%).

m.p. 146-151° C.

Example 75

To a solution of2-bromo-1-(3-bromophenyl)-2-[2-(tert-butoxycarbonylamino)-4-pyridyl]ethanonehydrobromide (22 g, 51 mmol) in N,N,-dimethylformamide (100 mL) wasadded thiopropionamide (4.3 g, 49 mmol), and the mixture was stirred for2 hours at room temperature. Into the reaction mixture was poured anaqueous sodium hydrogen carbonate solution, and extracted with ethylacetate. The extracts were washed with water, then, dried andconcentrated. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate=4:1), then, recrystallized fromhexane-ethyl acetate to obtain4-(3-bromophenyl)-5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-1,3-thiazole(6.0 g, yield 27%) and5-(2-amino-4-pyridyl)-4-(3-bromophenyl)-2-ethyl-1,3-thiazole (1.4 g,yield 8%).

Example Compound 75-1

4-(3-bromophenyl)-5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-1,3-thiazole

m.p. 172-174° C.

Example Compound 75-2

4-[4-(3-bromophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 132-134° C.

Example 76

4-[4-(3-cyanophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridylamine

To a solution of4-(3-bromophenyl)-5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-1,3-thiazole(0.5 g, 1.1 mmol) in N,N-dimethylformamide (10 mL) was added coppercyanide (0.25 g, 1.6 mmol), and the mixture was stirred for 20 hours at150° C. under argon atmosphere. Into the reaction mixture was pouredammonia water, and the deposit was removed, then, extracted with ethylacetate. The extracts were washed with water, then, dried andconcentrated. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate=4:1) to obtain a crystal. Thiscrystal was washed with hexane-ethyl acetate to obtain a title compound(0.19 g, yield 57%).

m.p. 178-179° C.

Example 77

3-[5-(2-amino-4-pyridyl)-2-ethyl-1,3-thiazol-4-yl]benzoic acid

To a solution of5-(2-amino-4-pyridyl)-4-(3-cyanophenyl)-2-ethyl-1,3-thiazole (0,50 g,1.6 mmol) in acetic acid (5 mL) was added 50% sulfuric acid (2.0 mL),and the mixture was stirred for 6 hours at 110° C. The reaction mixturewas basified with aqueous sodium hydroxide solution and washed withethylacetate. The aqueous phase was neutralized with hydrochloric acid,and the deposited crystal was washed with water and ethyl ether toobtain a title compound (0.45 g, yield 84%).

m.p. 273-274° C.

Example 78

Methyl 3-[5-(2-amino-4-pyridyl)-2-ethyl-1,3-thiazol-4-yl]benzoate

To a solution of3-[5-(2-amino-4-pyridyl)-4-(3-cyanophenyl)-2-ethyl-1,3-thiazol-4-yl]benzoicacid (0.3 g, 1.0 mmol) in methanol (10 mL) was added concentratedsulfuric acid (0.1 mL) and the mixture was stirred for 5 hours at 70° C.The reaction mixture was basified with sodium hydroxide solution andextracted with ethyl acetate. The extracts were washed with water, then,dried and concentrated. The residue was washed with hexane-ethyl acetateto obtain a title compound (0.29 g, yield 85%).

m.p. 173-174° C.

Example 79

To a solution of4-(3-bromophenyl)-5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-1,3-thiazole(1.0 g, 2.2 mmol) in tetrahydrofuran (20 mL) was added dropwise a 1.5 Mn-butyllithium hexane solution (2.9 mL, 4.3 mmol), and the mixture wasstirred for 15 minutes. The reaction mixture was poured onto dry ice,and extracted with ethyl acetate-tetrahydrofuran. The extracts werewashed with an aqueous sodium hydroxide solution, then, dried andconcentrated. The residue was recrystallized from hexane-ethyl acetateto obtain5-[2-(tert-butoxycarboylamino)-4-pyridyl]-2-ethyl-4-phenyl-1,3-thiazole(0.29 g, yield 35%). The aqueous layer was made acidic with hydrochloricacid, then, extracted with ethyl acetate-tetrahydrofuran. The extractswere washed with water, then, dried and concentrated. The residue waswashed with ethyl acetate to obtain[5-[2-(tert-butoxycarboylamino)-4-pyridyl]-2-ethyl-1,3-thiazol-4-yl]benzoicacid (0.21 g, yield 23%).

Example Compound 79-1

5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-4-phenyl-1,3-thiazole

m.p. 154-155° C.

Example Compound 79-2

3-[5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-1,3-thiazol-4-yl]benzoicacid

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=7.5 Hz), 1.45 (9H, s), 3.08 (2H, q,J=7.5 Hz), 6.83 (1H, dd, J=1.4, 5.0 Hz), 7,34-7.37 (2H, m), 7.42-7.49(2H, m), 7.86 (1H, s), 8.16 (1H, d, J=5.0 Hz), 9.91 (1H, s).

Example 80

4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine

A solution of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)ethanonehydrobromide (2.74 g, 8.36 mmol) and1-tert-butoxycarbonylpiperidine-4-carbothioamide inN,N-dimethylformamide (50 mL) was stirred at room temperature for 3hours. Aqueous sodium hydrogen carbonate was added to the reactionmixture and extracted with ethyl acetate. The extracts were washed withwater, dried, and concentrated. The residue was purified by silica gelcolumn chromatography (ethyl acetate) and then purified by columnchromatography (filler: Chromatorex NH DM1020 (trade name, manufacturedby Fuji Silysia Chemical Ltd.), ethyl acetate). The obtained crudecrystalline was recrystallized from ethyl acetate-hexane to give a titlecompound (1.94 g, yield 50%).

m.p. 143-145° C.

Example 81

N-[4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

To a solution of[4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine(1.60 g, 3.40 mmol) in tetrahydrofuran (20 mL) were added acetylchloride (0.25 mL, 3.52 mmol) and triethylamine (0.50 mL, 3.58 mmol) at0° C. sequentially, and the resulting mixture was stirred at roomtemperature for 3 hours. Aqueous sodium hydrogen carbonate was added tothe reaction mixture and extracted with ethyl acetate. The extracts werewashed with brine, dried, and concentrated. The residue was purified bycolumn chromatography (filler: Chromatorex NH DM1020 (trade name,manufactured by Fuji Silysia Chemical Ltd.), hexane-ethyl acetate=1:1)to give a title compound (1.79 g, yield 98%).

Amorphous Solid

¹H-NMR(CDCl₃) d: 1.49 (9H, s), 1.68-1.88 (2H, m), 2.13-2.21 (5H, m),2.91 (2H, br t, J=12.0 Hz), 3.12-3.25 (1H, m). 4.20-4.27 (2H, m), 6.87(1H, dd, J=1.8, 5.4 Hz), 7.18-7.35 (3H, m), 7.56 (1H, t, J=1.8 Hz), 8.15(1H, d, J=5.4 Hz), 8.27-8.33 (2H, m).

Example 82

The following reference example compounds 82-1 to 82-12 were synthesizedaccording to Example 81, using4-(2-ethyl-4-phenyl-1,3-thiazol-5-yl)-2-pyridylamine,4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(3-trifluoromethylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(4-fluoro-3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(3-fluorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(4-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(3-ethylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-[3-(1-methylethyl)phenyl]-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(3-propylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-methyl-4-(3methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine and4-[4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridylamine,respectively, instead of4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine.

Example Compound 82-1

N-[4-(2-ethyl-4-phenyl-1,3-thiazol-5-yl)-2-pyridyl]acetamide

m.p. 175-176° C.

Example Compound 82-2

N-[4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 190-191° C.

Example Compound 82-3

N-[4-[2-ethyl-4-(3-trifluoromethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 146-147° C.

Example Compound 82-4

N-[4-[2-ethyl-4-(4-fluoro-3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 142-143° C.

Example Compound 82-5

N-[4-[2-ethyl-4-(3-fluorophenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 141-142° C.

Example Compound 82-6

N-[4-[4-(4-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 190-191° C.

Example Compound 82-7

N-[4-[2-ethyl-4-(3-ethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 112-113° C.

Example Compound 82-8

N-[4-[2-ethyl-4-[3-(1-methylethyl)phenyl]-1,3thiazol-5-yl]-2-pyridyl]acetamide

m.p. 116-117° C.

Example Compound 82-9

N-[4-[2-ethyl-4-(3-propylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 121-122° C.

Example Compound 82-10

N-[4-[2-methyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 162-163° C.

Example Compound 82-11

N-[4-[4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 149-150° C.

Example Compound 82-12

N-[4-[4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 181-182° C.

Example 83

The following example compound 83 was synthesized according to Example81, using propionyl chloride instead of acetyl chloride.

Example Compound 83

N-[4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

Amorphous Solid

¹H-NMR(CDCl₃) d: 1.25 (3H, t, J=7.5 Hz), 1.49 (9H, s), 1.66-1.89 (2H,m), 2.08-2.22 (2H, m), 2.44 (2H, q, J=7.5 Hz), 2.82-3.00 (2H, m),3.11-3.24 (1H, m). 4.18-4.30 (2H, m), 6.84 (1H, dd, J=1.8, 5.0 Hz),7.19-7.36 (3H, m), 7.56. (1H, t, J=3.2 Hz), 8.13 (1H, d, J=5.0 Hz), 8.18(1H, br s), 8.33 (1H, s).

Example 84

The following reference example compounds 84-1 to 84-9 were synthesizedaccording to Example 83, using4-(2-ethyl-4-phenyl-1,3-thiazol-5-yl)-2-pyridylamine,4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(3-trifluoromethylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(4-fluoro-3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(3-fluorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(4-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-[3-(1-methylethyl)phenyl]-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(3-propylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine and4-[4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridylamine,respectively, instead of4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine.

Example Compound 84-1

N-[4-(2-ethyl-4-phenyl-1,3-thiazol-5-yl)-2-pyridyl]propionamide

m.p. 139-140° C.

Example Compound 84-2

N-[4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 156-157° C.

Example Compound 84-3

N-[4-[2-ethyl-4-(3-trifluoromethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 126-127° C.

Example Compound 84-4

N-[4-[2-ethyl-4-(4-fluoro-3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 105-107° C.

Example Compound 84-5

N-[4-[2-ethyl-4-(3-fluorophenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 121-122° C.

Example Compound 84-6

N-[4-[4-(4-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 152-153° C.

Example Compound 84-7

N-[4-[2-ethyl-4-[3-(1-methylethyl)phenyl]-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 93-94° C.

Example Compound 84-8

N-[4-[2-ethyl-4-(3-propylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 124-125° C.

Example Compound 84-9

N-[4-[4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 171-172° C.

Example 85

The following example compound 85 was synthesized according to Example28, using butyryl chloride instead of cyclohexanecarbonyl chloride.

Example Compound 85

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]butyramide

m.p. 88-89° C.

Example 86

The following example compound 86 was synthesized according to Example85, using 4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridylamineinstead of4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine.

Example Compound 86

N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]butyramide

m.p. 119-120° C.

Example 87

The following example compounds 87-1 and 87-2 were synthesized accordingto Example 85, using valeryl chloride and hexanoyl chloride,respectively, instead of butyryl chloride.

Example Compound 87-1

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]valeramide

m.p. 81-82° C.

Example Compound 87-2

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]hexanamide

m.p. 84-85° C.

Example 88

The following example compounds 88-1 and 88-2 were synthesized accordingto Example 86, using valeryl chloride and hexanoyl chloride,respectively, instead of butyryl chloride.

Example Compound 88-1

N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]valeramide

m.p. 109-110° C.

Example Compound 88-2

N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]hexanamide

m.p. 114-115° C.

Example 89

The following example compound 89 was synthesized according to Example28, using butyryl chloride instead of cyclopentylacetyl chloride.

Example Compound 89

N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]cyclopentylacetamide

m.p. 85-86° C.

Example 90

The following example compounds 90-1 and 90-2 were synthesized accordingto Example 89, using4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridylamine and4-[4-(4-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridylamine,respectively, instead of4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine.

Example Compound 90-1

N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]cyclopentylacetamide

m.p. 121-122° C.

Example Compound 90-2

N-[4-[4-(4-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]cyclopentylacetamide

m.p. 149-150° C.

Example 91

N-[4-[4-(3-chlorophenyl)-2-(4-piperidyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamidedihydrochloride

To a solution ofN-[4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylacetamide(1.44 g, 2.81 mmol) in methanol (10 mL) was added 2N-hydrochloric acid(4 mL) and stirred at 80° C. for an hour. The solvent was removed underreduced pressure and the residue was recrystallized from methanol togive a title compound (0.87 g, yield 64%).

m.p. 193-195° C.

Example 92

The following example compound 92 was synthesized according to Example91, usingN-[4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylpropionamideinstead ofN-[4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylacetamide.

Example Compound 92

N-[4-[4-(3-chlorophenyl)-2-(4-piperidyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamidedihydrochloride

m.p. 202-203° C.

Example 93

N-[4-[2-(1-acetylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

To a suspension ofN-[4-[4-(3-chlorophenyl)-2-(4-piperidyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamidedihydrochloride (0.41 g, 0.84 mmol) in tetrahydrofuran (20 mL) wereadded acetyl chloride (0.13 mL, 1.8 mmol) and triethylamine (0.50 mL,3.6 mmol) sequentially, and the resulting mixture was stirred at roomtemperature for 30 minutes. Aqueous sodium hydrogen carbonate was addedto the reaction mixture and extracted with ethyl acetate. The extractswere washed with water, dried, and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to give a title compound (0.24g, yield 62%).

m.p. 143-145° C.

Example 94

The following example compound 94 was synthesized according to Example93, usingN-[4-[4-(3-chlorophenyl)-2-(4-piperidyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamidedihydrochloride instead ofN-[4-[4-(3-chlorophenyl)-2-(4-piperidyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamidedihydrochloride.

Example Compound 94

N-[4-[2-(1-acetylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 174-175° C.

Example 95

The following example compound 95 was synthesized according to Example11, using 2-bromo-1-(3-ethylphenyl)-2-(2-fluoro-4-pyridyl)ethanonehydrobromide instead of2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide.

Example Compound 95

2-ethyl-4-(3-ethylphenyl)-5-(2-fluoro-4-pyridyl)-1,3-thiazole

Oil

¹H-NMR(CDCl₃) d: 1.18 (3H, t, J=7.6 Hz), 1.46 (3H, t, J=7.6 Hz), 2.62(2H, q, J=7.6 Hz), 3.10 (2H, q, J=7.6 Hz), 6.86 (1H, t, J=1.4 Hz), 7.07(1H, dt, J=1.4, 5.2 Hz), 7.16-7.30 (3H, m), 7.33 (1H, s), 8.10 (1H, d,J=5.2 Hz).

Example 96

N-cyclopentyl-4-[2-ethyl-4-(3-ethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

2-ethyl-4-(3-ethylphenyl)-5-(2-fluoro-4-pyridyl)-1,3-thiazole (0.51 g,1.6 mmol) and cyclopentylamine (1.6 mL, 16 mmol) were stirred at 140° C.for 12 hours. Aqueous sodium hydrogen carbonate was added to thereaction mixture and extracted with ethyl acetate. The extracts werewashed with aqueous sodium hydrogen carbonate and brine, in order,dried, and concentrated. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate=4:1). The obtained crudecrystalline was recrystallized from isopropyl ether to give a titlecompound (0.40 g, yield 66%).

m.p. 77-79° C.

Example 97

The following example compound 97 was synthesized according to Example96, using cyclohexylamine instead of cyclopentylamine.

Example Compound 97

N-cyclohexyl-4-[2-ethyl-4-(3-ethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

m.p. 115-116° C.

Example 98

The following example compounds 98-1 and 98-2 were synthesized accordingto Example 57, usingN-[4-[4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridyl]acetamideandN-[4-[4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazol-5-yl]-2-pyridyl]propionamide,respectively, instead of4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole.

Example Compound 98-1

N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 222-223° C.

Example Compound 98-2

N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 238-239° C.

Example 99

The following example compounds 99-1 and 99-2 were synthesized accordingto Example 17, using 3-(methylthio)thiopropionamide and2-amino-1-methyl-2-thioxoethyl benzoate instead of2-chlorothiobenzamide.

Example Compound 99-1

4-[4-(3-methylphenyl)-2-[2-(methylthio)ethyl]-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 98-99° C.

Example Compound 99-2

1-[5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3thiazol-2-yl]ethylbenzoate

m.p. 89-91° C.

Example 100

The following example compounds 100-1 and 100-2 were synthesizedaccording to Example 99, using2-(2-amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)ethanone hydrobromideinstead of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanonehydrobromide.

Example Compound 100-1

4-[4-(3-chlorophenyl)-2-[2-(methylthio)ethyl]-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 96-97° C.

Example Compound 100-2

1-[5-(2-amino-4-pyridyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]ethylbenzoate

Amorphous

¹H-NMR(CDCl₃) d: 1.89 (3H, d, J=6.4 Hz), 4.50 (2H, br s), 6.38-6.47 (2H,m), 6.56 (1H, dd, J=1.4, 5.6 Hz), 7.23-7.38 (3H, m), 7.45-7.53 (2H, m),7.58-7.66 (2H, m), 8.01 (1H, d, J=5.6 Hz), 8.11-8.16 (2H, m).

Example 101

The following example compounds 101-1 and 101-2 were synthesizedaccording to Example 100, using (methylthio)thioacetamide and2,2-difluorothiopropionamide instead of 3-(methylthio)thiopropionamide.

Example Compound 101-1

4-[4-(3-chlorophenyl)-2-(methylthio)methyl-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 111-112° C.

Example Compound 101-2

4-[4-(3-chlorophenyl)-2-(1,1-difluoroethyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 131-132° C.

Example 102

The following example compounds 102-1 to 102-6 were synthesizedaccording to Example 83, using4-[4-(3-methylphenyl)-2-[2-(methylthio)ethyl]-1,3-thiazol-5-yl]-2-pyridylamine,4-[4-(3-chlorophenyl)-2-[2-(methylthio)ethyl]-1,3-thiazol-5-yl]-2-pyridylamine,4-[4-(3-chlorophenyl)-2-(methylthio)methyl-1,3-thiazol-5-yl]-2-pyridylamine,4-[4-(3-chlorophenyl)-2-(1,1-difluoroethyl)-1,3-thiazol-5-yl]-2-pyridylamine,1-[5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]ethylbenzoate and1-[5-(2-amino-4-pyridyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]ethylbenzoate respectively, instead of4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine.

Example Compound 102-1

N-[4-[4-(3-methylphenyl)-2-[2-(methylthio)ethyl]-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 85-86° C.

Example Compound 102-2

N-[4-[4-(3-chlorophenyl)-2-[2-(methylthio)ethyl]-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 91-92° C.

Example Compound 102-3

N-[4-[4-(3-chlorophenyl)-2-(methylthio)methyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 118-119° C.

Example Compound 102-4

N-[4-[4-(3-chlorophenyl)-2-(1,1-difluoroethyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 141-142° C.

Example Compound 102-5

1-[4-(3-methylphenyl)-5-(2-propionylamino-4-pyridyl)-1,3-thiazol-2-yl]ethylbenzoate

m.p. 102-103° C.

Example Compound 102-6

1-[4-(3-chlorophenyl)-5-(2-propionylamino-4-pyridyl)-1,3-thiazol-2-yl]ethylbenzoate

m.p. 124-127° C.

Example 103

The following example compounds 103-1 and 103-2 were synthesizedaccording to Example 81, using1-[5-(2-amino-4-pyridyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]ethylbenzoate and ethyl[5-(2-amino-4-pyridyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]acetateinstead of[4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine.

Example Compound 103-1

1-[5-(2-acetylamino-4-pyridyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]ethylbenzoate

m.p. 152-154° C.

Example Compound 103-2

ethyl[5-(2-acetylamino-4-pyridyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]acetate

m.p. 99-100° C.

Example 104

N-[4-[2-(1-hydroxyethyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

An 1N aqueous sodium hydroxide solution was added dropwise to a solutionof1-[4-(3-methylphenyl)-5-(2-propionylamino-4-pyridyl)-1,3-thiazol-2-yl]ethylbenzoate (1.63 g, 3.46 mmol) in methanol (5 mL) and tetrahydrofuran (20mL) at 0° C. and the reaction mixture was allowed to warm up to roomtemperature. The resulting mixture was stirred at room temperature for30 minutes and the solvent was removed under reduced pressure. Theresidue was treated with aqueous sodium hydrogen carbonate solution andextracted with ethyl acetate. The extracts were washed with aqueoussodium hydrogen carbonate solution and brine. The resulting solution wasdried, and concentrated under reduced pressure. The obtained crudecrystal was recrystallized from ethyl acetate-hexane to give a titlecompound (1.12 g, yield 89%).

m.p. 115-116° C.

Example 105

The following example compound 105 was synthesized according to Example104, using1-[4-(3-chlorophenyl)-5-(2-propionylamino-4-pyridyl)-1,3-thiazol-2-yl]ethylbenzoate instead of1-[4-(3-methylphenyl)-5-(2-propionylamino-4-pyridyl)-1,3-thiazol-2-yl]ethylbenzoate.

Example Compound 105

N-[4-[4-(3-chlorophenyl)-2-(1-hydroxyethyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 131-132° C.

Example 106

N-[4-[2-acetyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

A solution of dimethylsulfoxide (0.30 mL, 4.2 mmol) in dichloromethane(1.0 mL) was added to a solution of oxalyl chloride (0.11 mL, 1.26 mmol)at −78° C. and the resulting mixture was stirred for 15 minutes. Asolution ofN-[4-[2-(1-hydroxyethyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide(0.38 g, 1.0 mmol) in dichloromethane (1.5 mL) was added to the mixtureand the resulting mixture was stirred for 45 minutes. The reactionmixture was allowed to warm up to −50° C. and triethylamine (0.72 mL,5.17 mmol) was added dropwise to the mixture. The resulting mixture wasstirred for 30 minutes and poured into aqueous sodium hydrogencarbonate. The mixture was extracted with ethyl acetate and the extractswere washed with aqueous sodium hydrogen carbonate solution and brine.The resulting solution was dried, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane-ethyl acetate=2:1) to obtain a crude crystal. The obtained crudecrystal was recrystallized from isopropyl ether to give a title compound(0.22 g, yield 58%).

m.p. 121-123° C.

Example 107

The following example compound 107 was synthesized according to Example106, usingN-[4-[4-(3-chlorophenyl)-2-(1-hydroxyethyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamideinstead ofN-[4-[2-(1-hydroxyethyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide.

Example Compound 107

N-[4-[2-acetyl-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide

m.p. 115-117° C.

Example 108

N-ethyl-N′-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]urea

To A solution of4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.50 g,1.7 mmol) in N,N-dimethylacetamide (10 mL) was added ethyl isocyanate(0.20 mL, 2.5 mmol) and the reaction mixture was stirred at 80° C. for20 hours. The reaction mixture was poured into aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The extracts were washedwith aqueous sodium hydrogen carbonate solution and brine. The resultingsolution was dried, and concentrated under reduced pressure. Theobtained crude crystal was recrystallized from ethyl acetate-hexane togive a title compound (0.29 g, yield 47%).

m.p. 160-162° C.

Example 109

The following example compound 109 was synthesized according to Example108, using4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridylamine insteadof 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine.

Example Compound 109

N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]-N′-ethyl-urea

m.p. 177-180° C.

Example 110

The following example compound 110 was synthesized according to Example81, using1-[5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]ethylbenzoate instead of[4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine.

Example Compound 110

1-[5-(2-acetylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]ethylbenzoate

m.p. 110-113° C.

Example 111

The following example compounds 111-1 and 111-2 were synthesizedaccording to Example 104, using1-[5-(2-acetylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]ethylbenzoate and1-[5-(2-acetylamino-4-pyridyl)-4-(3-chlorophenyl)-1,3-thiazol-2-yl]ethylbenzoate instead of1-[4-(3-methylphenyl)-5-(2-propionylamino-4-pyridyl)-1,3-thiazol-2-yl]ethylbenzoate.

Example Compound 111-1

N-[4-[2-(1-hydroxyethyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 99-102° C.

Example Compound 111-2

N-[4-[4-(3-chlorophenyl)-2-(1-hydroxyethyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 142-145° C.

Example 112

The following example compound 112 was synthesized according to Example106, usingN-[4-[4-(3-chlorophenyl)-2-(1-hydroxyethyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamideinstead ofN-[4-[2-(1-hydroxyethyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide.

Example Compound 112

N-[4-[2-acetyl-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide

m.p. 180-183° C.

Example 113

The following example compounds 113-1 and 113-2 were synthesizedaccording to Example 101, using2-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone hydrobromideinstead of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)ethanonehydrobromide

Example Compound 113-1

4-[4-(3-methylphenyl)-2-(methylthio)methyl-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 113-114° C.

Example Compound 113-2

4-[2-(1,1-difluoroethyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

m.p. 140-141° C.

The compounds produced in Examples 1 to 113 are shown in Tables 1 to 20.

TABLE 1

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 1 —NH₂

251-254 2 —NH₂

>270 (dec) 3 —CH₂Me

162-163 6 —NH₂

214-218 7-1 —NH₂

190-191 7-2 —NH₂

227-228 7-3 —NH₂

243-245 7-4 —NH₂

205-206 7-5 —NH₂

219-220 7-6 —NH₂

214-216 7-7 —NH₂

256-258 7-8 —NH₂

233-234 8 —NHMe

186-187

TABLE 2

Example Compound No. R_(a) R_(b) R_(c) mp/° C.  9 —NHMe

164-165 10 —NMe₂

77-79 11 —CH₂Me

oil 12 —CH₂Me

102-103 13 —CH₂Me

oil 14-1

83-84 14-2

104-105 14-3

73-74 14-4

89-91 14-5

90-91 14-6

79-80 14-7

82-84 14-8

64-65 14-9

oil

TABLE 3

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 14-10 —(CH₂)₃Me

oil 14-11 —(CH₂)₂Me

oil 14-12 —CO₂CH₂Me

97-98 14-13

115-116 14-14

127-130 15

 97-100 16-1 

119-122 16-2 

123-125 16-3 

112-114 16-4 

134-136 16-5 

 99-100 16-6 

183-184 17

175-177

TABLE 4

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 18-1

160-162 18-2 —(CH₂)₃Me

oil 18-3 —CH₂CF₃

131-132 18-4 —(CH₂)₂Me

113-115 18-5 —CH₂CO₂CH₂Me

128-129 18-6 —CO₂CH₂Me

147-148 20-1 —CH₂Me

131-132 20-2 —CH₂Me

158-159 20-3 —CH₂Me

140-141 20-4 —CH₂Me

117-118 20-5 —CH₂Me

119-120 20-6 —CH₂Me

153-154 20-7 —CH₂Me

136-137 20-8 —CH₂Me

128 -129

TABLE 5

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 20-9  —CH₂Me

134-135 20-10 —CH₂Me

80-81 20-11 —CH₂Me

72-74 20-12 —CH₂Me

159-160 21-1  —(CH₂)₂Me

 99-100 21-2  —CH₂CO₂CH₂Me

154-155 22 —CH₂Me

144-146 23-1  —Me

152-153 23-2 

181-183 23-3  —Me

140-141 24 —CH₂CO₂H

132-133 25-1  —CO₂H

156-157 25-2  —CO₂H

135-136 26 —H

oil

TABLE 6

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 27-1 —H

91-92 27-2 —Me

142-143 28 —CH₂Me

 98-100 29-1 —CH₂Me

123-125 29-2 —CH₂Me

119-120 29-3 —CH₂Me

oil 29-4 —CH₂Me

103-104 29-5 —CH₂Me

oil 30-1 —Me

112-115 30-2 —CH₂Me

149-150 30-3 —(CH₂)₂Me

144-145 30-4 —CH₂Me

154-155 30-5

207-208

TABLE 7

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 30-6 —CH₂Me

oil 30-7 —Me

134-135 30-8 —CH₂Me

132-133 30-9 —(CH₂)₂Me

103-104  30-10 —CH₂Me

187-188  30-11

187-188  30-12

119-120 31 —CH₂Me

74-75 32 —CH₂Me

67-69 33 —NH₂

181-182 34-1 —NH₂

188-189 34-2 —NH₂

168-169

TABLE 8

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 34-3 —NH₂

169-170 35-1 —NH₂

206-208 35-2

155-157 36-1 —NH₂

194-195 36-2 —NHMe

211-212 36-3 —NHMe

170-172 36-4 —CH₂Me

110-112 36-5

197-199 36-6 —CH₂Me

117-118 36-7

154-156 36-8

200-202

TABLE 9

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 36-9 —CH₂Me

69-71  36-10 —CH₂Me

106-107  36-11 —CH₂Me

110-111 37-1 —CH₂Me

108-109 37-2

173-174 37-3

157-159 37-4

199-201 37-5

153-154 38 —NHCOMe

262-264 39 —NHCOMe

230-231 40-1 —NHCOMe

236-237

TABLE 10

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 40-2 —NHCOMe

185-187 40-3 —NHCOMe

266-267 41

175-178 42-1

203-206 42-2

267-268 42-3

201-203 42-4

215-216 42-5

136-138 42-6

229-231 42-7

261-262 42-8

147-148

TABLE 11

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 42-9

148-149 42-10

oil 43

228-230 44-1

255-256 44-2

211-212 44-3

271-273 44-4

171-172 45

233-234 46-1

242-243 46-2

213-214 46-3

252-253 46-4

176-177

TABLE 12

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 47

224-226 48-1

191-192 48-2

219-221 48-3

242-244 49

169-170 50 —NHCOMe

247-250 51

219-222 52

173-174 53-1

219-222 53-2

198-199 53-3

188-190 53-4

168-169

TABLE 13

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 54

128-130 55

133-134 56-1

151-153 56-2

151-154 57

134-138 58-1

196-197 58-2

182-184 58-3

217-220 58-4

195-199 58-5

190-192 58-6

216-217 58-7

224-225

TABLE 14

Example Compound No. R_(a) R_(b) R_(c) additives mp/° C. 58-8

122-123 59

255-256 60

2HCl 248-253 61 —NHCONH(CH₂)₂Cl

149-151 62 —NHCO₂(CH₂)₂Cl

156-158 63 —NHCONHOMe

194-195 64

154-155 65

80-82 66

200-201 67

180-182 68-1

197-198 68-2 —CH₂Me

oil 69 —CH₂Me

oil

TABLE 15

Example Compound No. R_(a) R_(b) R_(c) additives mp/° C. 70-1 —CH₂Me

oil 70-2 —CH₂Me

oil 71 —CH₂Me

 68-69 72

172-173 73

2HCl amorphous 74 —CH₂Me

2HCl 146-151 75-1 —CH₂Me

172-174 75-2 —CH₂Me

132-134 76 —CH₂Me

178-179 77 —CH₂Me

273-274 78 —CH₂Me

173-174 79-1 —CH₂Me

154-155 79-2 —CH₂Me

amorphous

TABLE 16

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 80

143-145 81

amorphous 82-1 —CH₂Me

175-176 82-2 —CH₂Me

190-191 82-3 —CH₂Me

146-147 82-4 —CH₂Me

142-143 82-5 —CH₂Me

141-142 82-6 —CH₂Me

190-191 82-7 —CH₂Me

112-113 82-8 —CH₂Me

118-117 82-9 —CH₂Me

121-122 82-10 —Me

162-163 82-11 —H

149-150 82-12

181-182

TABLE 17

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 83

amorphous 84-1 —CH₂Me

139-140 84-2 —CH₂Me

156-157 84-3 —CH₂Me

126-127 84-4 —CH₂Me

105-107 84-5 —CH₂Me

121-122 84-6 —CH₂Me

152-153 84-7 —CH₂Me

93-94 84-8 —CH₂Me

124-125 84-9

171-172 85 —CH₂Me

88-89 86 —CH₂Me

119-120 87-1 —CH₂Me

81-82

TABLE 18

Example Compound No. R_(a) R_(b) R_(c) additives mp/° C. 87-2 —CH₂Me

84-85 88-1 —CH₂Me

109-110 88-2 —CH₂Me

114-115 89 —CH₂Me

85-86 90-1 —CH₂Me

121-122 90-2 —CH₂Me

149-150 91

2HCl 193-195 92

2HCl 202-203 93

160-161 94

174-175 95 —CH₂Me

oil 96 —CH₂Me

77-79 97 —CH₂Me

115-116

TABLE 19

Example Compound No. R_(a) R_(b) R_(c) mp/° C.  98-1

222-223  98-2

238-239  99-1 —CH₂CH₂SMe

98-99  99-2

89-91 100-1 —CH₂CH₂SMe

96-97 100-2

amorphous 101-1 —CH₂SMe

111-112 101-2 —CF₂Me

131-132 102-1 —CH₂CH₂SMe

85-86 102-2 —CH₂CH₂SMe

91-92 102-3 —CH₂SMe

118-119 102-4 —CF₂Me

141-142 102-5

102-103 102-6

124-127

TABLE 20

Example Compound No. R_(a) R_(b) R_(c) mp/° C. 103-1

152-154 103-2 —CH₂CO₂CH₂Me

 99-100 104 —CH(OH)Me

115-116 105 —CH(OH)Me

131-132 106 —COMe

121-123 107 —COMe

115-117 108 —CH₂Me

177-180 109 —CH₂Me

160-162 110

110-113 111-1 —CH(OH)Me

 99-102 111-2 —CH(OH)Me

142-145 112 —COMe

180-183 113-1 —CH₂SMe

113-114 113-2 —CF₂Me

140-141

Preparation Example 1

(1) Example compound 29-2 10.0 mg (2) Lactose 60.0 mg (3) Corn starch35.0 mg (4) Gelatin  3.0 mg (5) Magnesium stearate  2.0 mg

10.0 mg of Example Compound 29-2, 60.0 mg of lactose and 35.0 mg of Cornstarch are granulated through a 1 mm mesh sieve using 0.03 ml of a 10%gelatin aqueous solution (3.0 g in terms of gelatin), then, dried at 40°C. and sieved again. Thus obtained granules are mixed with 2.0 mg ofmagnesium stearate and compressed. The resulted core tablets are coatedwith sugar coating made from a water suspension of sucrose, titaniumdioxide, talc and Arabic gum. The coated tables are endowed with glossby bees wax to give coated tablets.

Preparation Example 2

(1) Example compound 29-2 10.0 mg (2) Lactose 70.0 mg (3) Corn starch50.0 mg (4) Soluble starch  7.0 mg (5) Magnesium stearate  3.0 mg

10.0 mg of Example Compound 29-2 and 3.0 mg of magnesium stearate aregranulated with 0.07 ml of an aqueous solution of soluble starch (7.0 mgin terms of soluble starch), then, dried, and mixed with 70.0 mg oflactose and 50.0 mg of corn starch. The mixture is compressed to obtaintablets.

Preparation Example 3

(1) Example compound 29-2  5.0 mg (2) Sodium Chloride 20.0 mg (3)Distilled water

amount to give total amount of 2 ml

5.0 mg of Example compound 29-2 and 20.0 mg of sodium chloride aredissolved in distilled water, and to this was added water to give atotal amount of 2.0 ml. The solution is filtrated, and a 2 ml ampule isfilled with the filtrate under sterile condition. The ampule isdisinfected, then, sealed to give an injection solution.

Reference Preparation Example 1

(1) Lofecoxiv  5.0 mg (2) Sodium chloride 20.0 mg (3) Distilled water

amount to give total amount of 2 ml

5.0 mg of lofecoxiv and 20.0 mg of sodium chloride are dissolved indistilled water, and to this is added water to give a total amount of2.0 ml. The solution is filtrated, and a 2 ml ampule is filled with thefiltrate under sterile condition. The ampule is disinfected, then,sealed to give an injection solution.

Reference Preparation Example 2

(1) Lofecoxiv   50 mg (2) Lactose   34 mg (3) Corn starch 10.6 mg (4)Corn starch (paste)   5 mg (5) Magnesium stearate  0.4 mg (6) Calciumcarboxymethylcellulose   20 mg Total  120 mg

The above-described components (1) to (6) are mixed according to anormal method, and tabletted by a tabletting machine to obtain tablets.

Preparation Example 4

Any of preparations of Preparation Examples 1 to 3 and any ofpreparations of Reference Preparation Examples 1 and 2 are combined.

Experiment 1

Genetic manipulation methods described below are based on methodsdescribed in Maniatis et al., Molecular Cloning, ColdSpring HarborLaboratory, 1989, and the appended reagent protocol.

(1) Cloning of Human p38 MAP Kinase Gene and Preparation of RecombinantBaculovirus

Cloning of human p38 MAP kinase gene was conducted by a PCR method usingprimer set p38-U: 5′-

[SEQ ID No. 1] ACCACTCGAGATGGACTACAAGGACGACGATGACAAGTCTCAGGAGAGGCCCACGTTCTACC-3′ and [SEQ ID No. 2] PAG-L:5′-ACCCGGTACCACCAGGTGCTCAGGACTCCATCTCT-3′synthesized referring to the nucleotide sequence of p38 MAP kinase geneof Han et al., Science 265 (5173), 808-811 (1994), utilizing kidney cDNA(QUICK-Clone cDNA, manufactured by Toyobo Co., Ltd.) as a template.

A PCR reaction was performed according to Hot Start method usingAmpliWax PCR Gem 100 (Takara Shuzo Co., Ltd.). For preparing lower layermixed liquid, 2 μL of 10×LA PCR Buffer, 3 μL of 2.5 mM dNTP solution,each 2.5 μL of 12.5 μM primer solution, and 10 μL of sterile distilledwater were mixed. For preparing upper layer mixed liquid, 1 μL of humanheart cDNA (1 ng/mL) as a template, 3 μL of 10×LA PCR Buffer, 1 μL of2.5 mM dNTP solution, 0.5 μL of TaKaRa LA Taq DNA polymerase (TakaraShuzo Co., Ltd.) and 24.5 μL of sterile distilled water were mixed. Tothe prepared lower mixed liquid was added one AmpliWax PCR Gem 100(Takara Shuzo Co., Ltd.) treated for 5 minutes at 70° C. and 5 minutesin ice, then, the upper mixed liquid was added, to prepare a reactionsolution for PCR. A tube filled with the reaction solution was set onThermal Cycler (Perkin Elmer), then, treated for 2 minutes at 95° C.Further, a cycle including 15 seconds at 95° C. and 2 minutes at 68° C.was repeated 35 times, then, treated for 8 minutes at 72° C. Theresulted PCR product was subjected to agarose gel (1%) electrophoresis,a 1.1 kb DNA fragment containing a p38 MAP kinase gene was recoveredfrom the gel, then, pT7Blue-T vector (Takara Shuzo Co., Ltd.) wasinserted to prepare a plasmid pHP38.

4.8 kb XhoI-KpnI fragment of plasmid pFASTBAC1 (CIBCOBRL) and 1.1 kbXhoI-Kpn fragment of the above-mentioned plasmid pHP38 were ligated toconstruct plasmid pFBHP38.

Plasmid pFBHP38 and BAC-TO-BAC Baculovirus Expression System (GIBCOBRL)were used to prepare virus stock BAC-HP38 of recombinant baculovirus.

(2) Cloning of Human MKK3 Gene and Preparation of RecombinantBaculovirus

Cloning of human MKK3 gene was conducted by a PCR method using primerset MKK-U: 5′-

[SEQ ID No. 3] ACAAGAATTCATAACATATGGCTCATCATCATCATCATCATTCCAAGCCACCCGCACCCAA-3′ and [SEQ ID No. 4] TCCCGTCTAGACTATGAGTCTTCTCCCAGGAT-3′synthesized referring to the nucleotide sequence of MKK3 gene ofDerijard, B. et al., Science 267 (5198), 682-685 (1995), utilizingkidney cDNA (QUICK-Clone cDNA, manufactured by Toyobo Co., Ltd.) as atemplate.

A PCR reaction was performed according to Hot Start method usingAmpliWax PCR Gem 100 (Takara Shuzo Co., Ltd.). For preparing lower layermixed liquid, 2 μL of 10×LA PCR Buffer, 3 μL of 2.5 mM dNTP solution,each 2.5 μL of 12.5 μM primer solution, and 10 μL of sterile distilledwater were mixed. For preparing upper layer mixed liquid, 1 μL of humankidney cDNA (1 ng/mL) as a template, 3 μL of 10×LA PCR Buffer, 1 μL of2.5 mM dNTP solution, 0.5 μL of TaKaRa LA Taq DNA polymerase (TakaraShuzo Co., Ltd.) and 24.5 μL of sterile distilled water were mixed. Tothe prepared lower mixed liquid was added one AmpliWax PCR Gem 100(Takara Shuzo Co.,Ltd.), treated for 5 minutes at 70° C. and 5 minutesin ice, then, the upper mixed liquid was added, to prepare a reactionsolution for PCR. A tube filled with the reaction solution was set onThermal Cycler (Perkin Elmer), then, treated for 2 minutes at 95° C.Further, a cycle including 15 seconds at 95° C. and 2 minutes at 68° C.was repeated 35 times, then, treated for 8 minutes at 72° C. Theresulted PCR product was subjected to agarose gel (1%) electrophoresis,a 1.0 kb DNA fragment containing a MKK3 gene was recovered from the gel,then, pT7Blue-T vector (Takara Shuzo Co., Ltd.) was inserted to preparea plasmid pHMKK3.

For converting MKK3 into constitutively active type (Ser at 189 isconverted into Glu, and. Thr at 193 is converted into Glu), mutation wasintroduced by QuikChange Site-Directed Mutagenesis Kit (Stratagene)using primer set SER-U: 5′-

GGCTACTTGGTGGACGAGGTGGCCAAGGAGATGGATGCCGGCTGC-3′ and [SEQ ID No. 5]SER-L: 5′-GCAGCCGGCATCCATCTCCTTGGCCACCTCGTCCACCAAGTAGCC-3′, [SEQ ID No.6] to obtain pcaMKK3.

4.8 kb EcoRI-XbaI fragment of plasmid pFASTBAC1 (CIBCOBRL) and 1.0 kbEcoRI-XbaI fragment of the above-mentioned plasmid pcaMKK3 were ligatedto construct plasmid pFBcaMKK3.

Plasmid pFBcaMKK3 and BAC-TO-BAC Baculovirus Expression System(GIBCOBRL) were used to prepare virus stock BAC-caMKK3 of recombinantbaculovirus.

(3) Preparation of Active Type p38 MAP Kinase

Sf-21 cells were inoculated on 100 mL Sf-900II SF medium (GIBCOBRL) togive 1×10⁶ cells/mL, then, cultured for 24 hours at 27° C. Each 0.2 mLof virus stocks BAC-HP38 and BAC-caMKK3 of the recombinant baculoviruswere added, then, cultured for further 48 hours. Cells were separatedfrom the culture solution by centrifugal separation (3000 rpm, 10 min.),then, washed with PBS twice. The cells were suspended in 10 mL of Lysisbuffer (25 mM HEPES (pH7.5), 1% TritonX, 130 mM NaCl, 1 mM EDTA, 1 mMDTT, 25 mM β-glycerophosphate, 20 mM leupeptin, 1 mM APMSF, 1 mM Sodiumorthovanadate), then, treatment by Homogenizer (POLYTRON) for 2 minutesat 20000 rpm was performed twice to lyse the cells. Active type p38 MAPkinase was purified from the supernatant obtained by centrifugalseparation (40000 rpm, 45 minutes), by using Anti-FLAG M2 Affinity Gel(Eastman Chemical).

(4) To 37.5 μL of a reaction solution (25 mM HEPES (pH 7.5), 10 mMMagnesium Acetate) containing 260 ng of active type p38 MAP kinase and 1μg of Myelin Basic Protein was added 2.5 μL of a sample compounddissolved in DMSO, then, the mixture was kept at 30° C. for 5 minutes.The reaction was initiated by adding 10 μL of an ATP solution (2.5 μMATP, 0.1 μCi[γ-³²P] ATP). After reaction for 60 minutes at 30° C., thereaction was terminated by adding 50 μL of a 20% TCA solution. Thereaction solution was left for 20 minutes at 0° C., then, acid insolublefraction was transferred to GF/C filter (Packard Japan) using CellHarvester (Packard Japan), and washed with 250 mM H₃PO₄. After dryingfor 60 minutes at 45° C., 40 μL of Microscint 0 (Packard Japan) wasadded, and radiation activity was measured by Top Counter (PackardJapan). The concentration (IC₅₀ value) of a sample compound necessaryfor inhibiting 50% of incorporation into the acid insoluble fraction of³²p was calculated by PRISM 2.01 (GraphPad Software).

The results are shown below.

TABLE 21 Example Compound No. IC₅₀ (μM) 30-2  0.010  34-2  0.0099 36-100.0011 46-4  0.017  58-7  0.0084Experiment 2

Measurement of Inhibitory Activity of TNF-α Production

THP-1 cells cultured in a PRMI 1640 medium (Life Technologies, Inc.,USA) containing 1% inactivated fetal bovine serum (Life Technologies,Inc.) and 10 mM HEPES (pH 7.5) were inoculated on a 96 well plate togive 1×10⁵ cells/well, then, 1 μL of a sample compound dissolved in DMSOwas added. After incubation for 1 hour at 37° C. in a CO₂ incubator, LPS(Wako Pure Chemical Industries Ltd.) was added to give a finalconcentration of 5 μg/mL. After incubation for 4 hours at 37° C. in aCO₂ incubator, the supernatant was obtained by centrifugal separation.The TNF-α concentration in the supernatant was measured by ELISA (R&DSystems, Quantikine Kit). The concentration (IC₅₀ value) of a samplecompound necessary for inhibiting 50% of TNF-α production was calculatedby PRISM 2.01 (GraphPad Software).

The results are shown below.

TABLE 22 Example Compound No. IC₅₀ (μM) 30-2  0.12  34-2  0.002 36-100.055 46-4  0.082 58-7  0.021

From the above-described results, it is known that compounds of thepresent invention have excellent inhibitory activity of p38 MAP kinaseand TNF-α production.

INDUSTRIAL APPLICABILITY

The compound (Ia), (Ib) or (Ic) of the present invention or a saltthereof or a pro-drug thereof has an excellent p38 MAP kinase inhibitoryactivity, TNF-α inhibitory activity and the like, and can be used as apharmaceutical composition for preventing or treating cytokine-mediateddiseases such as p38 MAP kinase-mediated diseases, TNF-α-mediateddiseases and the like, and as a pharmaceutical composition forpreventing or treating adenosine receptor-mediated diseases.

1. A compound which is:5-[2(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-4-(3-methylphenyl)-1,3-thiazole,[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine,2-ethyl-5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole,5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole,4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole,4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide,N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide,N-[4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide,N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide,N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]acetamide,N-[4-[4-(3-chlorophenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide,N-[4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide,N-[4-[4-(3-chlorophenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]propionamide,N-cyclohexyl-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,N-cyclohexyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,N-cyclopentyl-4-[-2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,N-cyclopentyl-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclohexyl-2-pyridylamine,4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-cyclopentyl-2-pyridylamine,N-[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]acetamide,4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-(4-methylsulfinylphenyl)-1,3-thiazole,4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole,5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole,N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide,N-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide,orN-[4-[4-(3-chlorophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]pivalamide,or a salt thereof.
 2. A pharmaceutical composition comprising thecompound as claimed in claim 1 and a pharmacologically acceptablecarrier.